Pathogenesis of Nonalcoholic Steatohepatitis and Hormone-Based Therapeutic Approaches

Abstract

Non-alcoholic fatty liver disease (NAFLD) is an emerging global health problem and a potential risk factor for type 2 diabetes, cardiovascular disease, and chronic kidney disease. Nonalcoholic steatohepatitis (NASH), an advanced form of NAFLD, is a predisposing factor for development of cirrhosis and hepatocellular carcinoma. The increasing prevalence of NASH emphasizes the need for novel therapeutic approaches. Although therapeutic drugs against NASH are not yet available, fundamental insights into the pathogenesis of NASH have been made during the past few decades. Multiple therapeutic strategies have been developed and are currently being explored in clinical trials or preclinical testing. The pathogenesis of NASH involves multiple intracellular/extracellular events in various cell types in the liver or crosstalk events between the liver and other organs. Here, we review current findings and knowledge regarding the pathogenesis of NASH, focusing on the most recent advances. We also highlight hormone-based therapeutic approaches for treatment of NASH.

Keywords: NAFLD; NASH; fibrosis; inflammation; multiple-parallel hit; steatosis.

Figure 1

The “mutiple-parallel hit” model in the pathogenesis of NASH. Three factors (environmental, metabolic and genetic factors) contribute to the development and progression of NASH by affecting diverse organs such as the liver, the intestine, and adipose tissue. In particular, excess caloric or inappropriate intake (environmental factor) increases toxic free fatty acid (FFA) and lipid metabolites (LPC, cholesterol and ceramide) in hepatocytes, leading to hepatic steatosis and hepatocyte sublethal/lethal injuries. Subsequently, hepatocyte-derived factors (such as cytokines/chemokines, DAMPs and extracellular vesicles) stimulate inflammatory response in Kupffer cell and fibrotic response in HSC, which leads to the development of inflammation and fibrosis in the liver. FFA and lipid metabolites derived from diets or synthesized de novo also activates Kupffer cell and HSC. In addition, insulin resistance and obesity (metabolic factor) influence organ-crosstalk between the intestine/adipose tissue and the liver, contributing to the development and progression of NASH.