Mitochondrial Cholesterol Metabolites in a Bile Acid Synthetic Pathway Drive Nonalcoholic Fatty Liver Disease: A Revised Two-Hit Hypothesis

The rising prevalence of nonalcoholic fatty liver disease (NAFLD)-related cirrhosis highlights the need for a better understanding of the molecular mechanisms responsible for driving the transition of hepatic steatosis (fatty liver; NAFL) to steatohepatitis (NASH) and fibrosis/cirrhosis. Obesity-related insulin resistance (IR) is a well-known hallmark of early NAFLD progression, yet the mechanism linking aberrant insulin signaling to hepatocyte inflammation has remained unclear. Recently, as a function of more distinctly defining the regulation of mechanistic pathways, hepatocyte toxicity as mediated by hepatic free cholesterol and its metabolites has emerged as fundamental to the subsequent necroinflammation/fibrosis characteristics of NASH. More specifically, aberrant hepatocyte insulin signaling, as found with IR, leads to dysregulation in bile acid biosynthetic pathways with the subsequent intracellular accumulation of mitochondrial CYP27A1-derived cholesterol metabolites, (25R)26-hydroxycholesterol and 3fi-Hydroxy-5-cholesten-(25R)26-oic acid, which appear to be responsible for driving hepatocyte toxicity. These findings bring forth a two-hit interpretation as to how NAFL progresses to NAFLD: abnormal hepatocyte insulin signaling, as occurs with IR, develops as a first hit that sequentially drives the accumulation of toxic CYP27A1-driven cholesterol metabolites as the second hit. In the following review, we examine the mechanistic pathway by which mitochondria-derived cholesterol metabolites drive the development of NASH. Insights into mechanistic approaches for effective NASH intervention are provided.

Automated summary

The rising prevalence of NAFLD-related cirrhosis emphasizes the importance of understanding the molecular mechanisms involved in the progression from hepatic steatosis to steatohepatitis and fibrosis/cirrhosis. Insulin resistance is a known factor in early NAFLD, but the link between aberrant insulin signaling and hepatocyte inflammation has been unclear. Recent research has shown that hepatocyte toxicity caused by hepatic free cholesterol and its metabolites is fundamental to the development of NASH. Specifically, abnormal hepatocyte insulin signaling leads to dysregulation in bile acid biosynthetic pathways and the accumulation of toxic cholesterol metabolites, driving hepatocyte toxicity. This two-hit model highlights the importance of both abnormal insulin signaling and the accumulation of toxic cholesterol metabolites in NAFL progression.