Mouse Models of Nonalcoholic Steatohepatitis: Toward Optimization of Their Relevance to Human Nonalcoholic Steatohepatitis

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.

Nonalcoholic fatty liver disease (NAFLD) is a condition in which excess fat accumulates in the liver of a patient without a history of alcohol abuse. Nonalcoholic steatohepatitis (NASH), a severe form of NAFLD, can progress to liver cirrhosis and hepatocellular carcinoma. NAFLD is regarded as a hepatic manifestation of metabolic syndrome and incidence has been increasing worldwide in line with the increased prevalence of obesity, type 2 diabetes, and hyperlipemia. Animal models of NAFLD/NASH give crucial information, not only in elucidating pathogenesis of NAFLD/NASH but also in examining therapeutic effects of various agents. An ideal model of NAFLD/NASH should correctly reflect both hepatic histopathology and pathophysiology of human NAFLD/NASH. Animal models of NAFLD/NASH are divided into genetic, dietary, and combination models. In this paper, we review commonly used animal models of NAFLD/NASH referring to their advantages and disadvantages.

Lipids encompass a wide variety of molecules such as fatty acids, sterols, phospholipids, and triglycerides. These molecules represent a highly efficient energy resource and can act as structural elements of membranes or as signaling molecules that regulate metabolic homeostasis through many mechanisms. Cells possess an integrated set of response systems to adapt to stresses such as those imposed by nutrient fluctuations during feeding-fasting cycles. While lipids are pivotal for these homeostatic processes, they can also contribute to detrimental metabolic outcomes. When metabolic stress becomes chronic and adaptive mechanisms are overwhelmed, as occurs during prolonged nutrient excess or obesity, lipid influx can exceed the adipose tissue storage capacity and result in accumulation of harmful lipid species at ectopic sites such as liver and muscle. As lipid metabolism and immune responses are highly integrated, accumulation of harmful lipids or generation of signaling intermediates can interfere with immune regulation in multiple tissues, causing a vicious cycle of immune-metabolic dysregulation. In this review, we summarize the role of lipotoxicity in metaflammation at the molecular and tissue level, describe the significance of anti-inflammatory lipids in metabolic homeostasis, and discuss the potential of therapeutic approaches targeting pathways at the intersection of lipid metabolism and immune function.