Lipotoxicity and the gut-liver axis in NASH pathogenesis

Summary

The pathogenesis of non-alcoholic fatty liver disease, particularly the mechanisms whereby a minority of patients develop a more severe phenotype characterised by hepatocellular damage, inflammation, and fibrosis is still incompletely understood. Herein, we discuss two pivotal aspects of the pathogenesis of NASH. We first analyse the initial mechanisms responsible for hepatocellular damage and inflammation, which derive from the toxic effects of excess lipids. Accumulating data indicate that the total amount of triglycerides stored in hepatocytes is not the major determinant of lipotoxicity, and that specific lipid classes act as damaging agents on liver cells. In particular, the role of free fatty acids such as palmitic acid, cholesterol, lysophosphatidylcholine and ceramides has recently emerged. These lipotoxic agents affect the cell behaviour via multiple mechanisms, including activation of signalling cascades and death receptors, endoplasmic reticulum stress, modification of mitochondrial function, and oxidative stress. In the second part of this review, the cellular and molecular players involved in the cross-talk between the gut and the liver are considered. These include modifications to the microbiota, which provide signals through the intestine and bacterial products, as well as hormones produced in the bowel that affect metabolism at different levels including the liver. Finally, the activation of nuclear receptors by bile acids is analysed.

Introduction

Non-alcoholic fatty liver disease (NAFLD) is an expanding health problem, with an estimated global prevalence of 25%.¹ NAFLD is associated with obesity, insulin resistance or type 2 diabetes and other metabolic abnormalities, collectively termed the metabolic syndrome. NAFLD encompasses a spectrum of conditions including simple steatosis and non-alcoholic steatohepatitis (NASH), characterised by hepatocellular damage, inflammation and fibrosis, which is a significant risk factor for the development of cirrhosis and hepatocellular carcinoma (HCC).² A critical aspect in the pathogenesis and natural history of NAFLD is the development of hepatic fibrosis, which has been recognised as a factor contributing to liver-related and all-cause mortality.³ As with other chronic liver diseases, fibrosis is the result of a long-standing wound healing process caused by hepatocellular injury. This in turn activates local inflammatory cells, recruits leukocytes from the bloodstream and activates myofibroblasts, mostly derived from transdifferentiation of hepatic stellate cells.⁴ NAFLD is characterised by the accumulation of different lipid species within hepatocytes. The consequent hepatocellular damage is linked to the accumulation of toxic lipids, resulting from a complex balance involving the liver and several other tissues, including the adipose tissue and the gut. The gut participates in lipotoxicity through the metabolism of nutrients and a number of secretory factors that eventually target the liver.⁴ Recent investigations have shown that changes in the microbiota have an impact on NAFLs pathogenesis and lipotoxicity, unveiling an additional type of interaction. Herein, we will discuss the major mechanisms leading to the generation of toxic lipid species that impact on the pathogenesis of NASH, and on the signalling mechanisms operating in this context. In addition, we will analyse the major pathways responsible for modulation of the so-called gut-liver axis during NASH, and their interaction with lipotoxic events.