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Pathophysiological Features of Rat Models of Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis

YASUKA SAIGO, KINUKO UNO, TATSUYA ISHIGURE, TATSUMI ODAKE and TAKESHI OHTA
In Vivo May 2024, 38 (3) 990-999; DOI: https://doi.org/10.21873/invivo.13532

Abstract

Nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) is caused by various factors, including genetic and/or environmental factors, and has complicated pathophysiological features during the development of the disease. NAFLD/NASH is recognized as an unmet medical need, and NAFLD/NASH animal models are essential tools for developing new therapies, including potential drugs and biomarkers. In this review, we describe the pathological features of the NAFLD/NASH rat models, focusing on the histopathology of hepatic fibrosis. NAFLD/NASH rat models are divided into three categories: diet-induced, genetic, and combined models based on diet, chemicals, and genetics. Rat models of NASH with hepatic fibrosis are especially expected to contribute to the development of new therapies, such as drugs and biomarkers.

Key Words:

The liver is the largest organ in the human body and performs various functions to maintain human health. Hepatic abnormalities in fatty liver disease include steatosis and steatosis-related liver damage. There are two types of fatty liver disease: alcoholic and nonalcoholic. Alcoholic fatty liver disease is caused by heavy alcohol consumption. However, the factors and mechanisms involved in the development of nonalcoholic fatty liver disease (NAFLD) are not fully understood. If not managed, both types of fatty liver disease progress to cirrhosis and liver cancer via hepatitis. NAFLD is a common liver disease worldwide with an alarmingly rapid prevalence (1-3). NAFLD is histopathologically classified as nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). NASH is a severe condition characterized by necroinflammation that progresses to cirrhosis and liver cancer. Animal models of NAFLD/NASH are pivotal in developing novel NAFLD/NASH therapies. The US Food and Drug Administration has provided guidance for the development of new drugs for the treatment of non-cirrhotic NASH with liver fibrosis, with no worsening of steatohepatitis and liver fibrosis as endpoints in clinical trials (https://www.fda.gov/media/119044/download). It is necessary to develop NAFLD/NASH models of hepatic inflammation/fibrosis and to understand the pathophysiological features of these models. NAFLD/NASH models can be divided into three categories: genetic, dietary, and chemical. In this review, we focus on dietary and genetic rat models that exhibit hepatic pathological features. We also describe the pathological changes in the combined models based on genetics, diet, and chemicals.

Diet-induced NAFLD/NASH Rat Models

Western diets and amino acid-modified diets are widely used to induce NAFLD/NASH-like lesions. Normal rats, such as Sprague-Dawley (SD) and Wistar rats, develop NAFLD/NASH-like changes, including steatosis, inflammation, and fibrosis, chiefly caused by western-style diets. Fischer 344 (F344) rats also develop NASH-like lesions following a choline-deficient, methionine-lowered, L-amino acid-defined (CDAA) diet. Pathological characteristics of diet-induced NAFLD/NASH rat models are summarized in Table I. Also, NAFLD/NASH-like lesions in genetic and combined with diet rat models are summarized in Table II.

View this table:
Table I.

Summary of pathological characteristics in diet-induced nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) rat models.

View this table:
Table II.

Summary of nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH)-like lesions in genetic and combined with diet rat models.

SD rats. Hepatic steatosis has been observed in SD rats consuming high-fat/high-cholesterol or high-fat/high-sucrose diets for 11-15 weeks; however, hepatic inflammation and fibrosis may or may not have been observed (4-7). In SD rats fed a high-fat diet for longer periods of 43 or 48 weeks, hepatic lobular inflammation and perisinusoidal fibrosis were observed after 36 weeks (8, 9). Hepatic inflammation and fibrosis were induced by the addition of cholic acid to a high-fat/high-cholesterol diet (10). In addition, early-onset NASH-like lesions were recently reported in SD rats fed a high-fat/high-cholesterol/cholic acid-containing diet with cyclodextrin water (11). Cyclodextrin water promotes cholesterol absorption from the diet.

Wistar rats. Many studies have reported developing models of experimental alcoholic liver disease in Wistar rats (12-15). Hepatic steatosis has been observed in Wistar rats consuming high-fat/high-cholesterol diets with added bile salt [10% fat (w/w), 2-3% cholesterol (w/w) and 0.3% bile acid (w/w)]. Hepatic inflammation has been observed between 9-16 weeks, but not in short term feeding (3 and 6 weeks) (16-18). In rats fed high-carbohydrate/high-fat diet [approximately 40-51.6% carbohydrate (w/w) and approximately 20-24% fat (w/w)] and fructose water (25% fructose (w/w)) for 8 or 16 weeks, hepatic steatosis and inflammation has been observed (19, 20). In the high-fat/high-cholesterol diet with added bile salt, feeding for 9-12 weeks did not induce fibrosis, but feeding for 16 weeks induced fibrosis (16-18). Also, the Wistar rats fed a high-carbohydrate/high-fat diet did not show fibrosis when fed for 16 weeks (20). To definitively evoke hepatic inflammation and fibrosis, a choline-deficient high-fat diet was fed to Wistar rats for 6-10 weeks (21-23). It is considered that the administration period or addition of cholesterol or modification of nutritional components are useful for inducing fibrosis.

F344 rats. Hepatic steatosis and inflammation have been observed in F344 rats fed a CDAA diet for more than a week (24, 25). Hepatic fibrosis was observed after four weeks, bridging fibrosis equivalent to stage 3 of Brunt’s NASH classification was formed after eight weeks, and significant bridging fibrosis was evident after 12 weeks (25, 26-29). In 2022, Uno et al. reported a significant increase in CD44 gene expression in the livers of F344 rats fed a CDAA diet (29). CD44 is an adhesion molecule that interacts with ligands including hyaluronic acid, collagen, and osteopontin. It has been shown to be associated with inflammation and fibrosis. As shown in Figure 1, cited from Uno et al. (29), CD44 was also expressed in intrahepatic bile duct epithelial cells and contributed to progress of hepatic fibrosis. The study demonstrated the potential of CD44 as a biomarker for NAFLD/NASH. There are few reports of dietary models other than the CDAA diet. High-fat diet [40% fat (w/w)] feeding for 13 weeks induced hepatic steatosis but inflammation was not observed (30). However, high-fat diet [16.2% fat (w/w)] feeding for 30 weeks induced both hepatic steatosis and inflammation (31). In either case, hepatic fibrosis was not demonstrated (30, 31). High-fat/-cholesterol diet (25% fat (w/w) and 1% cholesterol (w/w)) feeding for 8 weeks induced both hepatic steatosis and inflammation (32). When high-fructose diet [60% (w/w)] was fed for 13 weeks from 4 weeks of age, hepatic steatosis was observed, whereas when fed for 13 weeks from 12 weeks of age or fed for 18 weeks from 11 weeks of age, inflammation was also induced. In either case, hepatic fibrosis was not observed (30, 33). Feeding a western-style diet [16.4% fat (w/w), 11% cocoa butter (w/w) and 1% cholesterol (w/w)], for 26 weeks induced hepatic steatosis and inflammation, but no hepatic fibrosis (34). When iron was added to high-fat diet [16.2% fat (w/w) and 2.9% iron (w/w)] for 30 weeks, or western-style diet [16.4% fat (w/w), 11% cocoa butter (w/w), 1% cholesterol (w/w) and 6% iron (w/w)] for 26 weeks, hepatic steatosis and inflammation was induced but hepatic fibrosis was not observed (31, 34).

Figure 1.
Figure 1.

Liver histopathology. Immunohistochemical staining for CD44 in the liver of an F344 rat fed CDAA diet. (A) arrow head: CD44-positive inflammatory cells, (B) arrow head: CD44-positive intrahepatic bile duct epithelial cells. The black scale bar denotes 50 μm.

Genetic NAFLD/NASH Rat Models

Obese rats. Otsuka Long-Evans Tokushima Fatty (OLETF) rats. The OLETF rat model was established as an obese type 2 diabetes model by the Otsuka Pharmaceutical Company. Long-Evans Tokushima Otsuka (LETO) rats are the control animals. They originated from the same colony as the OLETF rats, but the LETO rats did not develop diabetes (35, 36). Male OLETF rats showed hepatic lipid accumulation with obesity and hyperinsulinemia at 8 weeks of age, and hepatic steatosis and vacuolization in male rats worsened until approximately 40 weeks of age in an age-dependent manner. Hepatic inflammatory cell infiltration and fibrosis were observed at 38 to 40 weeks of age in the OLETF rats fed Formulab Diet Purina Chow 5008 (containing 17% fat). Additionally, hepatocyte ballooning, nuclear displacement, and collagen deposition in perivenular regions were observed until approximately 40 weeks of age (37-40). In OLETF rats aged 55 weeks, basement membrane thickening was observed in hepatic blood vessels with sinusoidal fibrosis (41). There have also been reports of no fibrosis or collagen deposition in 42-week-old OLETF rats fed a standard rodent chow (containing 5.9% fat) (42).

Pathological changes in the liver have been observed in OLETF rats fed modified diets. A methionine- and choline-deficient (MCD) diet was used to promote NAFLD/NASH-like lesions in OLETF rats (43, 44). The MCD diet induced intense lobular inflammation, and perivenular and pericellular fibrosis evident in the OLETF rats, whereas it caused macrovesicular steatosis in LETO rats (45). A high-fat MCD diet has been used to create a state of insulin resistance and obesity in MCD dietary models (46). These authors also described significant steatohepatitis in OLETF rats. OLETF rats fed a western-style diet high in fat, sucrose, and cholesterol developed NASH-like lesions, such as hepatocyte ballooning, nuclear displacement, and bridging fibrosis, until 32 weeks of age (47).

Zucker Fatty (ZF) rats. ZF rats, which lack functional leptin receptors owing to missense mutations, show obesity, hyperinsulinemia, and lipid abnormalities (48, 49). ZF rats show excessive fat accumulation in the liver at 34 weeks of age (50). There are a few reports in which ZF rats fed a normal chow diet showed fibrosis in the liver. However, animals fed a western-style diet (high-fat, high-sucrose, and high-cholesterol) developed inflammation or fibrosis in the liver. Male ZF rats fed a high-fat diet for 4 weeks showed hepatic steatosis and fibrosis but did not show significant infiltration of inflammatory cells in the liver (51). Male ZF rats fed a high-fat/high-cholesterol diet for 4 to 12 weeks showed macrovesicular steatosis, intense lobular inflammation, and fibrosis in the liver (52, 53). Fibrosis and necrosis have been observed in the livers of male ZF rats fed a high-fat/high-sucrose/high-cholesterol diet for 18 weeks (54). Excessive cholesterol addition can exacerbate hepatic NAFLD/NASH-like lesions in ZF rats. Moreover, a synthetic diet rich in disaccharides (sucrose and lactose) was reported to induce hepatic fibrosis in ZF rats (55). Also, a CDAA diet-induced liver was examined in ZF (fa/fa) rats and their thin littermates (+/?), and the diet induced hepatic fibrosis in both rats and hepatocellular carcinoma was observed in littermate rats but not in ZF rats (56). Leptin signal deficiency in ZF rats may lead to poor response in hepatocellular carcinoma.

Zucker Diabetic Fatty (ZDF) rats. The origin of ZDF rats was a mutation that occurred in a colony of outbred ZF rats, and an inbred line of ZDF rats was established in 1985. ZDF rats develop insulin resistance, hyperinsulinemia, and diabetes (57). Male ZDF rats reportedly show hepatocyte ballooning injury with inflammatory cell infiltration and hepatic fibrosis at 22 weeks of age (58). At 32 weeks of age, male ZDF rats show patches of ballooning degeneration with no evidence of hepatic fibrosis (59). However, whether ZDF rats fed a normal chow diet develop hepatic fibrosis remains controversial. Male ZDF rats fed a high-fat diet for 21 weeks reportedly developed cholangiofibrosis and hepatic injury, including hepatocyte apoptosis (60).

SHR/NDmcr-cp (SHR-cp) rats. Spontaneously hypertensive SHR-cp rats develop metabolic syndrome-like abnormalities and reportedly show hepatic steatosis when fed AIN 93 diets containing 20% calories from casein, soy protein, or flaxseed meal for 6 months (61). There have been no reports of a high-fat dietary intervention.

Wistar Bonn Kobori (WBN/Kob) diabetic fatty rats. WBN/Kob diabetic fatty rats represent a congenic strain carrying the fa allele of the leptin receptor gene (Lepr) that exhibits obesity, insulin resistance, and diabetes (62, 63). WBN/Kob diabetic fatty rats fed a high-fructose diet for 4 weeks showed significant diffuse fatty degeneration (64). In addition, WBN/Kob diabetic fatty rats fed a high-fat diet for 4 weeks showed diffuse fatty changes with hepatocellular hypertrophy (65). However, there have been no reports of hepatic fibrosis in WBN/Kob rats.

Spontaneously Diabetic Torii (SDT) fatty rats. SDT fatty rats are an obese type 2 diabetic model established by introducing the fa gene of ZF rats into the SDT rat genome (66). SDT fatty rats show hyperphagia, obesity, and diabetes. The complications of these conditions develop at a younger age in SDT fatty rats than in SDT rats (67, 68). In female SDT fatty rats fed a normal diet, severe hepatosteatosis with inflammation was observed at 8 weeks of age, and hepatic fibrosis began to occur at 32 weeks of age (69). The onset of NASH-like lesions in SDT fatty rats was accelerated by dietary cholesterol loading, and hepatic fibrosis was observed at 16 weeks of age. At 24 weeks of age, rats fed a high-cholesterol diet for 20 weeks developed enhanced hepatic fibrosis (70, 71). Interestingly, NASH-like lesions, including hepatic fibrosis, were further accelerated in ovariectomized SDT fatty rats (72). Figure 2 and Figure 3 show representative images of hepatic fatty and vascular changes (Hematoxylin-eosin staining) and hepatic fibrosis (Sirius red staining) in female SD and SDT fatty rats at 24 weeks of age fed a high-cholesterol diet for 20 weeks.

Figure 2.
Figure 2.

Liver histopathology. Hematoxylin-eosin staining of the liver of a (A) female Sprague-Dawley (SD) rat fed a standard diet, (B) female SD rat fed a high-cholesterol diet, (C) female Spontaneously Diabetic Torii (SDT) fatty rat fed a standard diet, and (D) female SDT fatty rat fed a high-cholesterol diet. The white scale bar denotes 200 μm.

Figure 3.
Figure 3.

Liver histopathology. Sirius red staining of the liver of a (A) female Sprague-Dawley (SD) rat fed a standard diet, (B) female SD rat fed a high-cholesterol diet, (C) female Spontaneously Diabetic Torii (SDT) fatty rat fed a standard diet, and (D) female SDT fatty rat fed a high-cholesterol diet. The white scale bar denotes 200 μm.

Non-obese diabetic rats. Obesity is strongly associated with the development of NAFLD/NASH-like lesions. Non-obese diabetic rats develop hepatic steatosis only in combination with a western-style diet. However, hepatic fibrosis has not been detected in these rats.

Goto-Kakizaki (GK) rats, a non-obese type 2 diabetes model, show a spontaneous polygenic form of diabetes (73). Male GK rats fed a high-fat diet showed hepatic lipid accumulation (74, 75). GK rats fed a high-fat/high-cholesterol diet developed inflammatory cell infiltration in the liver with hepatic steatosis (76-78). Hepatic fibrosis was not observed in aged male GK rats (15 months old) fed a high-fat/high-cholesterol diet (79). SDT rats are a non-obese type 2 diabetic model. Male 42-week-old rats fed a high-fat diet showed hepatocellular adenoma with severe fatty changes (80).

Others. Recently, some reports have shown that high-fat diet-fed and streptozotocin (STZ)-treated mice showed NAFLD/NASH-like lesions, such as steatosis, inflammation, and fibrosis. Male SD rats 6 to 8 weeks of age developed NAFLD/NASH-like changes following the combination of a western-style diet and intraperitoneal injection of STZ (81-84). Additionally, male 4-5 months old SD rats fed a high-fat diet developed severe hepatocellular granular and vascular degeneration accompanied by necrotic and apoptotic cells in the liver of (85). Male and female Wistar rats also showed NAFLD/NASH-like lesions with a combination of a high-fat diet and STZ injection (86, 87).

Future Perspectives

An ideal animal model should mimic the pathophysiological features of human diseases as closely as possible. In NAFLD/NASH, where the mechanisms of pathogenesis and progression are not fully understood, it would be beneficial to elucidate the characteristics of the disease in animal models. In particular, animal models of NASH-like lesions with hepatic fibrosis are essential for studies on NAFLD/NASH. Although many pharmaceutical companies worldwide have attempted to develop drugs for NAFLD/NASH, none has been approved. Moreover, diabetes medications, such as pioglitazone and the antioxidant vitamin E, have been used in the treatment of NAFLD/NASH. However, their efficacy is limited (88). The effects of novel target factors and combination therapy with antidiabetic drugs on NAFLD/NASH have also been reported in animal models (89, 90). Several factors, including highly heterogeneous disease, complex pathology, and diagnostic biomarkers, contribute to the difficulty in developing NAFLD/NASH treatment. Periodic blood and urine collection is easy in rats, and rat models might be useful for investigating pathological changes and identifying new biomarkers of NAFLD/NASH. It is expected that NASH with hepatic fibrosis rat models will play key roles in developing new therapies and identifying new biomarkers for NAFLD/NASH.

Acknowledgements

The Authors would like to thank Wiley Editing Services (https://www.wileyeditingservices.com/en/) for English language editing.

Footnotes

  • Authors’ Contributions

    Yasuka Saigo: Conceptualization; Investigation; Project administration; Resources; Visualization; Roles/Writing – original draft. Kinuko Uno: Data curation; Investigation; Visualization; Roles/Writing – original draft; Writing – review & editing. Tatsuya Ishigure; Investigation; Visualization. Tatsumi Odake; Investigation; Visualization. Takeshi Ohta; Conceptualization; Data curation; Investigation; Project administration; Supervision; Visualization; Roles/Writing – original draft; Writing – review & editing.

  • Conflicts of Interest

    There are no conflicts of interest to declare in relation to this study.

  • Received February 1, 2024.
  • Revision received March 3, 2024.
  • Accepted March 4, 2024.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

References

  1. ↵
    1. Patel AH,
    2. Peddu D,
    3. Amin S,
    4. Elsaid MI,
    5. Minacapelli CD,
    6. Chandler TM,
    7. Catalano C,
    8. Rustgi VK
    : Nonalcoholic fatty liver disease in lean/nonobese and obese individuals: a comprehensive review on prevalence, pathogenesis, clinical outcomes, and treatment. J Clin Transl Hepatol 11(2): 502-515, 2023. DOI: 10.14218/JCTH.2022.00204
    OpenUrlCrossRef
    1. Murphy WA,
    2. Adiwidjaja J,
    3. Sjöstedt N,
    4. Yang K,
    5. Beaudoin JJ,
    6. Spires J,
    7. Siler SQ,
    8. Neuhoff S,
    9. Brouwer KLR
    : Considerations for physiologically based modeling in liver disease: from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH). Clin Pharmacol Ther 113(2): 275-297, 2023. DOI: 10.1002/cpt.2614
    OpenUrlCrossRef
  3. ↵
    1. Margini C,
    2. Dufour JF
    : The story of HCC in NAFLD: from epidemiology, across pathogenesis, to prevention and treatment. Liver Int 36(3): 317-324, 2016. DOI: 10.1111/liv.13031
    OpenUrlCrossRefPubMed
  4. ↵
    1. Mu Y,
    2. She R,
    3. Zhang H,
    4. Dong B,
    5. Huang C,
    6. Lin W,
    7. Li D,
    8. Li X
    : Effects of estrogen and androgen deprivation on the progression of non-alcoholic steatohepatitis (NASH) in male Sprague–Dawley rats. Hepatol Res 39(9): 910-920, 2009. DOI: 10.1111/j.1872-034X.2009.00512.x
    OpenUrlCrossRefPubMed
    1. Alisi A,
    2. Pastore A,
    3. Ceccarelli S,
    4. Panera N,
    5. Gnani D,
    6. Bruscalupi G,
    7. Massimi M,
    8. Tozzi G,
    9. Piemonte F,
    10. Nobili V
    : Emodin prevents intrahepatic fat accumulation, inflammation and redox status imbalance during diet-induced hepatosteatosis in rats. Int J Mol Sci 13(2): 2276-2289, 2012. DOI: 10.3390/ijms13022276
    OpenUrlCrossRefPubMed
    1. Wang HN,
    2. Wang YR,
    3. Liu GQ,
    4. Liu Z,
    5. Wu PX,
    6. Wei XL,
    7. Hong TP
    : Inhibition of hepatic interleukin-18 production by rosiglitazone in a rat model of nonalcoholic fatty liver disease. World J Gastroenterol 14(47): 7240-7246, 2008. DOI: 10.3748/wjg.14.7240
    OpenUrlCrossRefPubMed
  7. ↵
    1. Alisi A,
    2. Bruscalupi G,
    3. Pastore A,
    4. Petrini S,
    5. Panera N,
    6. Massimi M,
    7. Tozzi G,
    8. Leoni S,
    9. Piemonte F,
    10. Nobili V
    : Redox homeostasis and posttranslational modifications/activity of phosphatase and tensin homolog in hepatocytes from rats with diet-induced hepatosteatosis. J Nutr Biochem 23(2): 169-178, 2012. DOI: 10.1016/j.jnutbio.2010.11.013
    OpenUrlCrossRefPubMed
  8. ↵
    1. Omagari K,
    2. Kato S,
    3. Tsuneyama K,
    4. Inohara C,
    5. Kuroda Y,
    6. Tsukuda H,
    7. Fukazawa E,
    8. Shiraishi K,
    9. Mune M
    : Effects of a long-term high-fat diet and switching from a high-fat to low-fat, standard diet on hepatic fat accumulation in Sprague-Dawley rats. Dig Dis Sci 53(12): 3206-3212, 2008. DOI: 10.1007/s10620-008-0303-1
    OpenUrlCrossRefPubMed
  9. ↵
    1. Xu ZJ,
    2. Fan JG,
    3. Ding XD,
    4. Qiao L,
    5. Wang GL
    : Characterization of high-fat, diet-induced, non-alcoholic steatohepatitis with fibrosis in rats. Dig Dis Sci 55(4): 931-940, 2010. DOI: 10.1007/s10620-009-0815-3
    OpenUrlCrossRefPubMed
  10. ↵
    1. Niwa A,
    2. Kobayashi T,
    3. Moteki Y,
    4. Terashima H,
    5. Omura Y,
    6. Matsumoto K,
    7. Ono Y,
    8. Kawamata T
    : [A case of intraosseous meningioma suspected of osteosarcoma based on preoperative image examinations]. No Shinkei Geka 47(9): 969-975, 2019. DOI: 10.11477/mf.1436204056
    OpenUrlCrossRef
  11. ↵
    1. Saigo Y,
    2. Sasase T,
    3. Tohma M,
    4. Uno K,
    5. Shinozaki Y,
    6. Maekawa T,
    7. Sano R,
    8. Miyajima K,
    9. Ohta T
    : High-cholesterol diet in combination with hydroxypropyl-beta-cyclodextrin induces NASH-like disorders in the liver of rats. Physiol Res 72(3): 371-382, 2023. DOI: 10.33549/physiolres.934981
    OpenUrlCrossRef
  12. ↵
    1. Tsukamoto H,
    2. Towner SJ,
    3. Clofalo LM,
    4. French SW
    : Ethanol-induced liver fibrosis in rats fed high fat diet. Hepatology 6(5): 814-822, 1986. DOI: 10.1002/hep.1840060503
    OpenUrlCrossRefPubMed
    1. Nanji AA,
    2. Tsukamoto H,
    3. French SW
    : Relationship between fatty liver and subsequent development of necrosis, inflammation and fibrosis in experimental alcoholic liver disease. Exp Mol Pathol 51(2): 141-148, 1989. DOI: 10.1016/0014-4800(89)90014-2
    OpenUrlCrossRefPubMed
    1. Takeyama Y,
    2. Kamimura S,
    3. Kuroiwa A,
    4. Sohda T,
    5. Irie M,
    6. Shijo H,
    7. Okumura M
    : Role of Kupffer cell-derived reactive oxygen intermediates in alcoholic liver disease in rats in vivo. Alcohol Clin Exp Res 20(9 Suppl): 335A-339A, 1996.
    OpenUrlPubMed
  15. ↵
    1. Tsukamoto H
    : Oxidative stress, antioxidants, and alcoholic liver fibrogenesis. Alcohol 10(6): 465-467, 1993. DOI: 10.1016/0741-8329(93)90066-w
    OpenUrlCrossRefPubMed
  16. ↵
    1. Pan M,
    2. Song YL,
    3. Xu JM,
    4. Gan HZ
    : Melatonin ameliorates nonalcoholic fatty liver induced by high-fat diet in rats. J Pineal Res 41(1): 79-84, 2006. DOI: 10.1111/j.1600-079X.2006.00346.x
    OpenUrlCrossRefPubMed
    1. Zaitone S,
    2. Hassan N,
    3. El-Orabi N,
    4. El-Awady el-S
    : Pentoxifylline and melatonin in combination with pioglitazone ameliorate experimental non-alcoholic fatty liver disease. Eur J Pharmacol 662(1-3): 70-77, 2011. DOI: 10.1016/j.ejphar.2011.04.049
    OpenUrlCrossRefPubMed
  18. ↵
    1. Feng SZ,
    2. Tian JL,
    3. Zhang Q,
    4. Wang H,
    5. Sun N,
    6. Zhang Y,
    7. Chen BY
    : An experimental research on chronic intermittent hypoxia leading to liver injury. Sleep Breath 15(3): 493-502, 2011. DOI: 10.1007/s11325-010-0370-3
    OpenUrlCrossRefPubMed
  19. ↵
    1. Poudyal H,
    2. Panchal S,
    3. Brown L
    : Comparison of purple carrot juice and β-carotene in a high-carbohydrate, high-fat diet-fed rat model of the metabolic syndrome. Br J Nutr 104(9): 1322-1332, 2010. DOI: 10.1017/S0007114510002308
    OpenUrlCrossRefPubMed
  20. ↵
    1. Iyer A,
    2. Kauter K,
    3. Alam MA,
    4. Hwang SH,
    5. Morisseau C,
    6. Hammock BD,
    7. Brown L
    : Pharmacological inhibition of soluble epoxide hydrolase ameliorates diet-induced metabolic syndrome in rats. Exp Diabetes Res 2012: 758614, 2012. DOI: 10.1155/2012/758614
    OpenUrlCrossRefPubMed
  21. ↵
    1. Takayama F,
    2. Nakamoto K,
    3. Totani N,
    4. Yamanushi T,
    5. Kabuto H,
    6. Kaneyuki T,
    7. Mankura M
    : Effects of docosahexaenoic acid in an experimental rat model of nonalcoholic steatohepatitis. J Oleo Sci 59(8): 407-414, 2010. DOI: 10.5650/jos.59.407
    OpenUrlCrossRefPubMed
    1. Takayama F,
    2. Nakamoto K,
    3. Kawasaki H,
    4. Mankura M,
    5. Egashira T,
    6. Ueki K,
    7. Hasegawa A,
    8. Okada S,
    9. Mori A
    : Beneficial effects of Vitis coignetiae Pulliat leaves on nonalcoholic steatohepatitis in a rat model. Acta Med Okayama 63(2): 105-111, 2009. DOI: 10.18926/AMO/31835
    OpenUrlCrossRefPubMed
  23. ↵
    1. Pak W,
    2. Takayama F,
    3. Mine M,
    4. Nakamoto K,
    5. Kodo Y,
    6. Mankura M,
    7. Egashira T,
    8. Kawasaki H,
    9. Mori A
    : Anti-oxidative and anti-inflammatory effects of spirulina on rat model of non-alcoholic steatohepatitis. J Clin Biochem Nutr 51(3): 227-234, 2012. DOI: 10.3164/jcbn.12-18
    OpenUrlCrossRefPubMed
  24. ↵
    1. Nakae D
    : Endogenous liver carcinogenesis in the rat. Pathol Int 49(12): 1028-1042, 1999. DOI: 10.1046/j.1440-1827.1999.00990.x
    OpenUrlCrossRefPubMed
  25. ↵
    1. Kawaratani H,
    2. Tsujimoto T,
    3. Kitazawa T,
    4. Kitade M,
    5. Yoshiji H,
    6. Uemura M,
    7. Fukui H
    : Innate immune reactivity of the liver in rats fed a choline-deficient L-amino-acid-defined diet. World J Gastroenterol 14(43): 6655-6661, 2008. DOI: 10.3748/wjg.14.6655
    OpenUrlCrossRefPubMed
  26. ↵
    1. Fujita K,
    2. Nozaki Y,
    3. Yoneda M,
    4. Wada K,
    5. Takahashi H,
    6. Kirikoshi H,
    7. Inamori M,
    8. Saito S,
    9. Iwasaki T,
    10. Terauchi Y,
    11. Maeyama S,
    12. Nakajima A
    : Nitric oxide plays a crucial role in the development/progression of nonalcoholic steatohepatitis in the choline-deficient, l-amino acid-defined diet-fed rat model. Alcohol Clin Exp Res 34 Suppl 34(s1): S18-24, 2010. DOI: 10.1111/j.1530-0277.2008.00756.x
    OpenUrlCrossRefPubMed
    1. Tsujimoto T,
    2. Kawaratani H,
    3. Kitazawa T,
    4. Hirai T,
    5. Ohishi H,
    6. Kitade M,
    7. Yoshiji H,
    8. Uemura M,
    9. Fukui H
    : Decreased phagocytic activity of Kupffer cells in a rat nonalcoholic steatohepatitis model. World J Gastroenterol 14(39): 6036-6043, 2008. DOI: 10.3748/wjg.14.6036
    OpenUrlCrossRefPubMed
    1. Abe N,
    2. Tsuchida T,
    3. Yasuda SI,
    4. Oka K
    : Dietary iron restriction leads to a reduction in hepatic fibrosis in a rat model of non-alcoholic steatohepatitis. Biol Open 8(5): bio040519, 2019. DOI: 10.1242/bio.040519
    OpenUrlAbstract/FREE Full Text
  29. ↵
    1. Uno K,
    2. Miyajima K,
    3. Toma M,
    4. Suzuki-Kemuriyama N,
    5. Nakae D
    : CD44 expression in the bile duct epithelium is related to hepatic fibrosis in nonalcoholic steatohepatitis rats induced by a choline-deficient, methionine-lowered, L-amino acid diet. J Toxicol Pathol 35(2): 149-157, 2022. DOI: 10.1293/tox.2021-0069
    OpenUrlCrossRef
  30. ↵
    1. de Castro UG,
    2. dos Santos RA,
    3. Silva ME,
    4. de Lima WG,
    5. Campagnole-Santos MJ,
    6. Alzamora AC
    : Age-dependent effect of high-fructose and high-fat diets on lipid metabolism and lipid accumulation in liver and kidney of rats. Lipids Health Dis 12: 136, 2013. DOI: 10.1186/1476-511X-12-136
    OpenUrlCrossRefPubMed
  31. ↵
    1. Atarashi M,
    2. Izawa T,
    3. Miyagi R,
    4. Ohji S,
    5. Hashimoto A,
    6. Kuwamura M,
    7. Yamate J
    : Dietary iron supplementation alters hepatic inflammation in a rat model of nonalcoholic steatohepatitis. Nutrients 10(2): 175, 2018. DOI: 10.3390/nu10020175
    OpenUrlCrossRef
  32. ↵
    1. Pereira RR,
    2. de Abreu IC,
    3. Guerra JF,
    4. Lage NN,
    5. Lopes JM,
    6. Silva M,
    7. de Lima WG,
    8. Silva ME,
    9. Pedrosa ML
    : Açai (Euterpe oleracea Mart.) upregulates paraoxonase 1 gene expression and activity with concomitant reduction of hepatic steatosis in high-fat diet-fed rats. Oxid Med Cell Longev 2016: 8379105, 2016. DOI: 10.1155/2016/8379105
    OpenUrlCrossRef
  33. ↵
    1. Carvalho MMF,
    2. Reis LLT,
    3. Lopes JMM,
    4. Lage NN,
    5. Guerra JFDC,
    6. Zago HP,
    7. Bonomo LF,
    8. Pereira RR,
    9. Lima WG,
    10. Silva ME,
    11. Pedrosa ML
    : Açai improves non-alcoholic fatty liver disease (NAFLD) induced by fructose. Nutr Hosp 35(2): 318-325, 2018. DOI: 10.20960/nh.1294
    OpenUrlCrossRef
  34. ↵
    1. Fujiwara S,
    2. Izawa T,
    3. Mori M,
    4. Atarashi M,
    5. Yamate J,
    6. Kuwamura M
    : Dietary iron overload enhances Western diet induced hepatic inflammation and alters lipid metabolism in rats sharing similarity with human DIOS. Sci Rep 12(1): 21414, 2022. DOI: 10.1038/s41598-022-25838-3
    OpenUrlCrossRef
  35. ↵
    1. Kawano K,
    2. Hirashima T,
    3. Mori S,
    4. Saitoh Y,
    5. Kurosumi M,
    6. Natori T
    : Spontaneous long-term hyperglycemic rat with diabetic complications: Otsuka Long-Evans Tokushima Fatty (OLETF) strain. Diabetes 41(11): 1422-1428, 1992. DOI: 10.2337/diab.41.11.1422
    OpenUrlAbstract/FREE Full Text
  36. ↵
    1. Kawano K,
    2. Hirashima T,
    3. Mori S,
    4. Natori T
    : OLETF (Otsuka Long-Evans Tokushima Fatty) rat: a new NIDDM rat strain. Diabetes Res Clin Pract 24 Suppl: S317-S320, 1994. DOI: 10.1016/0168-8227(94)90269-0
    OpenUrlCrossRefPubMed
  37. ↵
    1. Rector RS,
    2. Thyfault JP,
    3. Uptergrove GM,
    4. Morris EM,
    5. Naples SP,
    6. Borengasser SJ,
    7. Mikus CR,
    8. Laye MJ,
    9. Laughlin MH,
    10. Booth FW,
    11. Ibdah JA
    : Mitochondrial dysfunction precedes insulin resistance and hepatic steatosis and contributes to the natural history of non-alcoholic fatty liver disease in an obese rodent model. J Hepatol 52(5): 727-736, 2010. DOI: 10.1016/j.jhep.2009.11.030
    OpenUrlCrossRefPubMed
    1. Sheldon RD,
    2. Laughlin MH,
    3. Rector RS
    : Reduced hepatic eNOS phosphorylation is associated with NAFLD and type 2 diabetes progression and is prevented by daily exercise in hyperphagic OLETF rats. J Appl Physiol (1985) 116(9): 1156-1164, 2014. DOI: 10.1152/japplphysiol.01275.2013
    OpenUrlCrossRefPubMed
    1. Rector RS,
    2. Uptergrove GM,
    3. Morris EM,
    4. Borengasser SJ,
    5. Laughlin MH,
    6. Booth FW,
    7. Thyfault JP,
    8. Ibdah JA
    : Daily exercise vs. caloric restriction for prevention of nonalcoholic fatty liver disease in the OLETF rat model. Am J Physiol Gastrointest Liver Physiol 300(5): G874-G883, 2011. DOI: 10.1152/ajpgi.00510.2010
    OpenUrlCrossRefPubMed
  40. ↵
    1. Chang E,
    2. Kim DH,
    3. Yang H,
    4. Lee DH,
    5. Bae SH,
    6. Park CY
    : CB1 receptor blockade ameliorates hepatic fat infiltration and inflammation and increases Nrf2-AMPK pathway in a rat model of severely uncontrolled diabetes. PLoS One 13(10): e0206152, 2018. DOI: 10.1371/journal.pone.0206152
    OpenUrlCrossRef
  41. ↵
    1. Tanaka T,
    2. Kono T,
    3. Terasaki F,
    4. Yasui K,
    5. Soyama A,
    6. Otsuka K,
    7. Fujita S,
    8. Yamane K,
    9. Manabe M,
    10. Usui K,
    11. Kohda Y
    : Thiamine prevents obesity and obesity-associated metabolic disorders in OLETF rats. J Nutr Sci Vitaminol (Tokyo) 56(6): 335-346, 2010. DOI: 10.3177/jnsv.56.335
    OpenUrlCrossRefPubMed
  42. ↵
    1. Song YS,
    2. Fang CH,
    3. So BI,
    4. Park JY,
    5. Lee Y,
    6. Shin JH,
    7. Jun DW,
    8. Kim H,
    9. Kim KS
    : Time course of the development of nonalcoholic Fatty liver disease in the Otsuka long-evans Tokushima Fatty rat. Gastroenterol Res Pract 2013: 342648, 2013. DOI: 10.1155/2013/342648
    OpenUrlCrossRef
  43. ↵
    1. Uno M,
    2. Kurita S,
    3. Misu H,
    4. Ando H,
    5. Ota T,
    6. Matsuzawa-Nagata N,
    7. Kita Y,
    8. Nabemoto S,
    9. Akahori H,
    10. Zen Y,
    11. Nakanuma Y,
    12. Kaneko S,
    13. Takamura T
    : Tranilast, an antifibrogenic agent, ameliorates a dietary rat model of nonalcoholic steatohepatitis. Hepatology 48(1): 109-118, 2008. DOI: 10.1002/hep.22338
    OpenUrlCrossRefPubMed
  44. ↵
    1. Kim M,
    2. Yang SG,
    3. Kim JM,
    4. Lee JW,
    5. Kim YS,
    6. Lee JI
    : Silymarin suppresses hepatic stellate cell activation in a dietary rat model of non-alcoholic steatohepatitis: analysis of isolated hepatic stellate cells. Int J Mol Med 30(3): 473-479, 2012. DOI: 10.3892/ijmm.2012.1029
    OpenUrlCrossRefPubMed
  45. ↵
    1. Kurita S,
    2. Takamura T,
    3. Ota T,
    4. Matsuzawa-nagata N,
    5. Kita Y,
    6. Uno M,
    7. Nabemoto S,
    8. Ishikura K,
    9. Misu H,
    10. Ando H,
    11. Zen Y,
    12. Nakanuma Y,
    13. Kaneko S
    : Olmesartan ameliorates a dietary rat model of non-alcoholic steatohepatitis through its pleiotropic effects. Eur J Pharmacol 588(2-3): 316-324, 2008. DOI: 10.1016/j.ejphar.2008.04.028
    OpenUrlCrossRefPubMed
  46. ↵
    1. Ota T,
    2. Takamura T,
    3. Kurita S,
    4. Matsuzawa N,
    5. Kita Y,
    6. Uno M,
    7. Akahori H,
    8. Misu H,
    9. Sakurai M,
    10. Zen Y,
    11. Nakanuma Y,
    12. Kaneko S
    : Insulin resistance accelerates a dietary rat model of nonalcoholic steatohepatitis. Gastroenterology 132(1): 282-293, 2007. DOI: 10.1053/j.gastro.2006.10.014
    OpenUrlCrossRefPubMed
  47. ↵
    1. Linden MA,
    2. Sheldon RD,
    3. Meers GM,
    4. Ortinau LC,
    5. Morris EM,
    6. Booth FW,
    7. Kanaley JA,
    8. Vieira-Potter VJ,
    9. Sowers JR,
    10. Ibdah JA,
    11. Thyfault JP,
    12. Laughlin MH,
    13. Rector RS
    : Aerobic exercise training in the treatment of non-alcoholic fatty liver disease related fibrosis. J Physiol 594(18): 5271-5284, 2016. DOI: 10.1113/JP272235
    OpenUrlCrossRef
  48. ↵
    1. Zucker LM
    : Fat mobilization in vitro and in vivo in the genetically obese Zucker rat “fatty”. J Lipid Res 13(2): 234-243, 1972.
    OpenUrlAbstract
  49. ↵
    1. Zucker LM
    : Efficiency of energy utilization by the Zucker hereditarily obese rat “fatty”. Proc Soc Exp Biol Med 148(2): 498-500, 1975. DOI: 10.3181/00379727-148-38569
    OpenUrlCrossRefPubMed
  50. ↵
    1. Toblli JE,
    2. Muñoz MC,
    3. Cao G,
    4. Mella J,
    5. Pereyra L,
    6. Mastai R
    : ACE inhibition and AT1 receptor blockade prevent fatty liver and fibrosis in obese Zucker rats. Obesity (Silver Spring) 16(4): 770-776, 2008. DOI: 10.1038/oby.2007.114
    OpenUrlCrossRefPubMed
  51. ↵
    1. Deushi M,
    2. Nomura M,
    3. Kawakami A,
    4. Haraguchi M,
    5. Ito M,
    6. Okazaki M,
    7. Ishii H,
    8. Yoshida M
    : Ezetimibe improves liver steatosis and insulin resistance in obese rat model of metabolic syndrome. FEBS Lett 581(29): 5664-5670, 2007. DOI: 10.1016/j.febslet.2007.11.023
    OpenUrlCrossRefPubMed
  52. ↵
    1. Matsunami T,
    2. Sato Y,
    3. Ariga S,
    4. Sato T,
    5. Kashimura H,
    6. Hasegawa Y,
    7. Yukawa M
    : Regulation of oxidative stress and inflammation by hepatic adiponectin receptor 2 in an animal model of nonalcoholic steatohepatitis. Int J Clin Exp Pathol 3(5): 472-481, 2010.
    OpenUrlPubMed
  53. ↵
    1. Matsunami T,
    2. Sato Y,
    3. Ariga S,
    4. Sato T,
    5. Shimomura T,
    6. Kashimura H,
    7. Hasegawa Y,
    8. Yukawa M
    : Regulation of synthesis and oxidation of fatty acids by adiponectin receptors (AdipoR1/R2) and insulin receptor substrate isoforms (IRS-1/-2) of the liver in a nonalcoholic steatohepatitis animal model. Metabolism 60(6): 805-814, 2011. DOI: 10.1016/j.metabol.2010.07.032
    OpenUrlCrossRefPubMed
  54. ↵
    1. Saito T,
    2. Toriniwa Y,
    3. Ishii Y,
    4. Uemura A,
    5. Miyajima K,
    6. Uno K,
    7. Shirai Y,
    8. Nakae D,
    9. Ohta T
    : Hepatic lesions induced by feeding Western diets to Zucker fatty rats, an insulin-resistant model. J Toxicol Pathol 31(4): 283-291, 2018. DOI: 10.1293/tox.2018-0016
    OpenUrlCrossRef
  55. ↵
    1. Fukunishi S,
    2. Nishio H,
    3. Fukuda A,
    4. Takeshita A,
    5. Hanafusa T,
    6. Higuchi K,
    7. Suzuki K
    : Long-term feeding of a synthetic diet rich in disaccharides induces hepatic fibrosis in nonalcoholic fatty liver disease in Zucker rats. Int J Mol Med 25(2): 187-193, 2010.
    OpenUrlPubMed
  56. ↵
    1. Kitade M,
    2. Yoshiji H,
    3. Kojima H,
    4. Ikenaka Y,
    5. Noguchi R,
    6. Kaji K,
    7. Yoshii J,
    8. Yanase K,
    9. Namisaki T,
    10. Asada K,
    11. Yamazaki M,
    12. Tsujimoto T,
    13. Akahane T,
    14. Uemura M,
    15. Fukui H
    : Leptin-mediated neovascularization is a prerequisite for progression of nonalcoholic steatohepatitis in rats. Hepatology 44(4): 983-991, 2006. DOI: 10.1002/hep.21338
    OpenUrlCrossRefPubMed
  57. ↵
    1. Unger RH
    : How obesity causes diabetes in Zucker diabetic fatty rats. Trends Endocrinol Metab 8(7): 276-282, 1997. DOI: 10.1016/s1043-2760(97)00094-5
    OpenUrlCrossRefPubMed
  58. ↵
    1. Salley TN,
    2. Mishra M,
    3. Tiwari S,
    4. Jadhav A,
    5. Ndisang JF
    : The heme oxygenase system rescues hepatic deterioration in the condition of obesity co-morbid with type-2 diabetes. PLoS One 8(11): e79270, 2013. DOI: 10.1371/journal.pone.0079270
    OpenUrlCrossRefPubMed
  59. ↵
    1. Sui Y,
    2. Kong X,
    3. Fan R,
    4. Ye Y,
    5. Mai H,
    6. Zhuo S,
    7. Lu W,
    8. Ruan P,
    9. Fang S,
    10. Yang T
    : Long-term treatment with metformin in the prevention of fatty liver in Zucker diabetic fatty rats. Diabetol Metab Syndr 11: 94, 2019. DOI: 10.1186/s13098-019-0491-1
    OpenUrlCrossRef
  60. ↵
    1. Kundu A,
    2. Dey P,
    3. Park JH,
    4. Kim IS,
    5. Kwack SJ,
    6. Kim HS
    : EX-527 prevents the progression of high-fat diet-induced hepatic steatosis and fibrosis by upregulating SIRT4 in Zucker rats. Cells 9(5): 1101, 2020. DOI: 10.3390/cells9051101
    OpenUrlCrossRef
  61. ↵
    1. Bhathena SJ,
    2. Ali AA,
    3. Haudenschild C,
    4. Latham P,
    5. Ranich T,
    6. Mohamed AI,
    7. Hansen CT,
    8. Velasquez MT
    : Dietary flaxseed meal is more protective than soy protein concentrate against hypertriglyceridemia and steatosis of the liver in an animal model of obesity. J Am Coll Nutr 22(2): 157-164, 2003. DOI: 10.1080/07315724.2003.10719289
    OpenUrlCrossRefPubMed
  62. ↵
    1. Akimoto T,
    2. Nakama K,
    3. Katsuta Y,
    4. Zhang XJ,
    5. Ohsuga M,
    6. Ishizaki M,
    7. Sawai N,
    8. Ozawa H
    : Characterization of a novel congenic strain of diabetic fatty (WBN/Kob-Leprfa) rat. Biochem Biophys Res Commun 366(2): 556-562, 2008. DOI: 10.1016/j.bbrc.2007.12.003
    OpenUrlCrossRefPubMed
  63. ↵
    1. Kaji N,
    2. Okuno A,
    3. Ohno-Ichiki K,
    4. Oki H,
    5. Ishizawa H,
    6. Shirai M,
    7. Asai F
    : Plasma profiles of glucose, insulin and lipids in the male WBN/Kob-Lepr(fa) rat, a new model of type 2 diabetes with obesity. J Vet Med Sci 74(9): 1185-1189, 2012. DOI: 10.1292/jvms.12-0045
    OpenUrlCrossRefPubMed
  64. ↵
    1. Namekawa J,
    2. Nemoto S,
    3. Sunada G,
    4. Takanashi Y,
    5. Fujio S,
    6. Shirai M,
    7. Asai F
    : Characteristics of WBN/Kob diabetic fatty rats supplemented with a fructose-rich diet as a metabolic syndrome model: response to a GLP-1 receptor agonist. J Vet Med Sci 80(10): 1515-1523, 2018. DOI: 10.1292/jvms.18-0306
    OpenUrlCrossRef
  65. ↵
    1. Kaji N,
    2. Takagi Y,
    3. Matsuda S,
    4. Takahashi A,
    5. Fujio S,
    6. Asai F
    : Effects of liraglutide on metabolic syndrome in WBN/Kob diabetic fatty rats supplemented with a high-fat diet. Animal Model Exp Med 3(1): 62-68, 2020. DOI: 10.1002/ame2.12106
    OpenUrlCrossRef
  66. ↵
    1. Masuyama T,
    2. Katsuda Y,
    3. Shinohara M
    : A novel model of obesity-related diabetes: Introgression of the Leprfa Allele of the Zucker fatty rat into nonobese spontaneously diabetic Torii (SDT) rats. Exp Anim 54(1): 13-20, 2005. DOI: 10.1538/expanim.54.13
    OpenUrlCrossRefPubMed
  67. ↵
    1. Ishii Y,
    2. Ohta T,
    3. Sasase T,
    4. Morinaga H,
    5. Ueda N,
    6. Hata T,
    7. Kakutani M,
    8. Miyajima K,
    9. Katsuda Y,
    10. Masuyama T,
    11. Shinohara M,
    12. Matsushita M
    : Pathophysiological analysis of female spontaneously diabetic Torii fatty rats. Exp Anim 59(1): 73-84, 2010. DOI: 10.1538/expanim.59.73
    OpenUrlCrossRefPubMed
  68. ↵
    1. Matsui K,
    2. Ohta T,
    3. Oda T,
    4. Sasase T,
    5. Ueda N,
    6. Miyajima K,
    7. Masuyama T,
    8. Shinohara M,
    9. Matsushita M
    : Diabetes-associated complications in spontaneously diabetic Torii fatty rats. Exp Anim 57(2): 111-121, 2008. DOI: 10.1538/expanim.57.111
    OpenUrlCrossRefPubMed
  69. ↵
    1. Ishii Y,
    2. Motohashi Y,
    3. Muramatsu M,
    4. Katsuda Y,
    5. Miyajima K,
    6. Sasase T,
    7. Yamada T,
    8. Matsui T,
    9. Kume S,
    10. Ohta T
    : Female spontaneously diabetic Torii fatty rats develop nonalcoholic steatohepatitis-like hepatic lesions. World J Gastroenterol 21(30): 9067-9078, 2015. DOI: 10.3748/wjg.v21.i30.9067
    OpenUrlCrossRef
  70. ↵
    1. Toriniwa Y,
    2. Muramatsu M,
    3. Ishii Y,
    4. Riya E,
    5. Miyajima K,
    6. Ohshida S,
    7. Kitatani K,
    8. Takekoshi S,
    9. Matsui T,
    10. Kume S,
    11. Yamada T,
    12. Ohta T
    : Pathophysiological characteristics of non-alcoholic steatohepatitis-like changes in cholesterol-loaded type 2 diabetic rats. Physiol Res 67(4): 601-612, 2018. DOI: 10.33549/physiolres.933784
    OpenUrlCrossRef
  71. ↵
    1. Toriniwa Y,
    2. Saito T,
    3. Miyajima K,
    4. Ishii Y,
    5. Uno K,
    6. Maekawa T,
    7. Matsui T,
    8. Kume S,
    9. Yamada T,
    10. Ohta T
    : Investigation of pharmacological responses to anti-diabetic drugs in female Spontaneously Diabetic Torii (SDT) fatty rats, a new nonalcoholic steatohepatitis (NASH) model. J Vet Med Sci 80(6): 878-885, 2018. DOI: 10.1292/jvms.18-0119
    OpenUrlCrossRef
  72. ↵
    1. Saigo Y,
    2. Sasase T,
    3. Uno K,
    4. Shinozaki Y,
    5. Maekawa T,
    6. Sano R,
    7. Toriniwa Y,
    8. Miyajima K,
    9. Ohta T
    : Establishment of a new nonalcoholic steatohepatitis model; Ovariectomy exacerbates nonalcoholic steatohepatitis-like pathology in diabetic rats. J Pharmacol Toxicol Methods 116: 107190, 2022. DOI: 10.1016/j.vascn.2022.107190
    OpenUrlCrossRef
  73. ↵
    1. Portha B,
    2. Serradas P,
    3. Bailbé D,
    4. Suzuki K,
    5. Goto Y,
    6. Giroix M
    : β-cell insensitivity to glucose in the GK rat, a spontaneous nonobese model for type II diabetes. Diabetes 40(4): 486-491, 1991. DOI: 10.2337/diab.40.4.486
    OpenUrlAbstract/FREE Full Text
  74. ↵
    1. Mine T,
    2. Miura K,
    3. Kajioka T,
    4. Kitahara Y
    : Nateglinide prevents fatty liver through up-regulation of lipid oxidation pathway in Goto-Kakizaki rats on a high-fat diet. Metabolism 57(1): 140-148, 2008. DOI: 10.1016/j.metabol.2007.08.017
    OpenUrlCrossRefPubMed
  75. ↵
    1. Almon RR,
    2. Dubois DC,
    3. Sukumaran S,
    4. Wang X,
    5. Xue B,
    6. Nie J,
    7. Jusko WJ
    : Effects of high fat feeding on liver gene expression in diabetic Goto-Kakizaki rats. Gene Regul Syst Bio 6: 151-168, 2012. DOI: 10.4137/GRSB.S10371
    OpenUrlCrossRef
  76. ↵
    1. Matafome P,
    2. Nunes E,
    3. Louro T,
    4. Amaral C,
    5. Crisóstomo J,
    6. Rodrigues L,
    7. Moedas AR,
    8. Monteiro P,
    9. Cipriano A,
    10. Seiça R
    : A role for atorvastatin and insulin combination in protecting from liver injury in a model of type 2 diabetes with hyperlipidemia. Naunyn Schmiedebergs Arch Pharmacol 379(3): 241-251, 2009. DOI: 10.1007/s00210-008-0363-y
    OpenUrlCrossRefPubMed
    1. Matafome P,
    2. Louro T,
    3. Rodrigues L,
    4. Crisóstomo J,
    5. Nunes E,
    6. Amaral C,
    7. Monteiro P,
    8. Cipriano A,
    9. Seiça R
    : Metformin and atorvastatin combination further protect the liver in type 2 diabetes with hyperlipidaemia. Diabetes Metab Res Rev 27(1): 54-62, 2011. DOI: 10.1002/dmrr.1157
    OpenUrlCrossRefPubMed
  78. ↵
    1. Torrado-Salmerón C,
    2. Guarnizo-Herrero V,
    3. Henriques J,
    4. Seiça R,
    5. Sena CM,
    6. Torrado-Santiago S
    : Multiparticulate systems of ezetimibe micellar system and atorvastatin solid dispersion efficacy of low-dose ezetimibe/atorvastatin on high-fat diet-induced hyperlipidemia and hepatic steatosis in diabetic rats. Pharmaceutics 13(3): 421, 2021. DOI: 10.3390/pharmaceutics13030421
    OpenUrlCrossRef
  79. ↵
    1. Sena CM,
    2. Cipriano MA,
    3. Botelho MF,
    4. Seiça RM
    : Lipoic acid prevents high-fat diet-induced hepatic steatosis in Goto Kakizaki rats by reducing oxidative stress through Nrf2 activation. Int J Mol Sci 19(9): 2706, 2018. DOI: 10.3390/ijms19092706
    OpenUrlCrossRef
  80. ↵
    1. Taniai-Riya E,
    2. Miyajima K,
    3. Kakimoto K,
    4. Ohta T,
    5. Yasui Y,
    6. Kemmochi Y,
    7. Anagawa-Nakamura A,
    8. Toyoda K,
    9. Takahashi A,
    10. Shoda T
    : Hepatocellular adenoma with severe fatty change in a male Spontaneously Diabetic Torii rat. J Toxicol Pathol 30(1): 69-73, 2017. DOI: 10.1293/tox.2016-0051
    OpenUrlCrossRef
  81. ↵
    1. Yu S,
    2. Cheng Y,
    3. Zhang L,
    4. Yin Y,
    5. Xue J,
    6. Li B,
    7. Gong Z,
    8. Gao J,
    9. Mu Y
    : Treatment with adipose tissue-derived mesenchymal stem cells exerts anti-diabetic effects, improves long-term complications, and attenuates inflammation in type 2 diabetic rats. Stem Cell Res Ther 10(1): 333, 2019. DOI: 10.1186/s13287-019-1474-8
    OpenUrlCrossRef
    1. El-Derany MO,
    2. El-Demerdash E
    : Pyrvinium pamoate attenuates non-alcoholic steatohepatitis: Insight on hedgehog/Gli and Wnt/β-catenin signaling crosstalk. Biochem Pharmacol 177: 113942, 2020. DOI: 10.1016/j.bcp.2020.113942
    OpenUrlCrossRef
    1. Gerges SH,
    2. Wahdan SA,
    3. Elsherbiny DA,
    4. El-Demerdash E
    : Diosmin ameliorates inflammation, insulin resistance, and fibrosis in an experimental model of non-alcoholic steatohepatitis in rats. Toxicol Appl Pharmacol 401: 115101, 2020. DOI: 10.1016/j.taap.2020.115101
    OpenUrlCrossRef
  84. ↵
    1. Hendawy AS,
    2. El-Lakkany NM,
    3. Mantawy EM,
    4. Hammam OA,
    5. Botros SS,
    6. El-Demerdash E
    : Vildagliptin alleviates liver fibrosis in NASH diabetic rats via modulation of insulin resistance, oxidative stress, and inflammatory cascades. Life Sci 304: 120695, 2022. DOI: 10.1016/j.lfs.2022.120695
    OpenUrlCrossRef
  85. ↵
    1. Aboulmagd YM,
    2. El-Bahy AA,
    3. Menze ET,
    4. Azab SS,
    5. El-Demerdash E
    : Role of linagliptin in preventing the pathological progression of hepatic fibrosis in high fat diet and streptozotocin-induced diabetic obese rats. Eur J Pharmacol 881: 173224, 2020. DOI: 10.1016/j.ejphar.2020.173224
    OpenUrlCrossRef
  86. ↵
    1. Pozzo L,
    2. Vornoli A,
    3. Coppola I,
    4. Croce CM,
    5. Giorgetti L,
    6. Gervasi PG,
    7. Longo V
    : Effect of HFD/STZ on expression of genes involved in lipid, cholesterol and glucose metabolism in rats. Life Sci 166: 149-156, 2016. DOI: 10.1016/j.lfs.2016.09.022
    OpenUrlCrossRef
  87. ↵
    1. Gopinath V,
    2. Shamsitha MKA,
    3. Penarveettil Nair V,
    4. Seena P,
    5. Uppu RM,
    6. C. Raghavamenon A
    : Thermally oxidized coconut oil as fat source in high-fat diet induces hepatic fibrosis in diabetic rat model. Cell Biochem Biophys 79(3): 629-639, 2021. DOI: 10.1007/s12013-021-01009-5
    OpenUrlCrossRef
  88. ↵
    1. Sumida Y,
    2. Yoneda M
    : Current and future pharmacological therapies for NAFLD/NASH. J Gastroenterol 53(3): 362-376, 2018. DOI: 10.1007/s00535-017-1415-1
    OpenUrlCrossRefPubMed
  89. ↵
    1. Tashiro Y,
    2. Han Q,
    3. Tan Y,
    4. Sugisawa N,
    5. Yamamoto J,
    6. Nishino H,
    7. Inubushi S,
    8. Sun YU,
    9. Lim H,
    10. Aoki T,
    11. Murakami M,
    12. Takahashi Y,
    13. Bouvet M,
    14. Hoffman RM
    : Oral recombinant methioninase prevents nonalcoholic fatty liver disease in mice on a high fat diet. In Vivo 34(3): 979-984, 2020. DOI: 10.21873/invivo.11866
    OpenUrlAbstract/FREE Full Text
  90. ↵
    1. Chiu HY,
    2. Tsai SC,
    3. Tsai FJ,
    4. Lo YH,
    5. Cheng CC,
    6. Liu TY,
    7. Jhan SR,
    8. Yang JS,
    9. Chiu YJ
    : Liraglutide with metformin therapy ameliorates hepatic steatosis and liver injury in a mouse model of non-alcoholic steatohepatitis. In Vivo 37(3): 1037-1046, 2023. DOI: 10.21873/invivo.13178
    OpenUrlAbstract/FREE Full Text
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Pathophysiological Features of Rat Models of Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis
YASUKA SAIGO, KINUKO UNO, TATSUYA ISHIGURE, TATSUMI ODAKE, TAKESHI OHTA
In Vivo May 2024, 38 (3) 990-999; DOI: 10.21873/invivo.13532
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