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

卷:12

Review

关键词: ACUTE-REGULATORY-PROTEIN;    OXYSTEROL 7-ALPHA-HYDROXYLASE GENE;    ENDOPLASMIC-RETICULUM STRESS;    INHIBIT CYTOCHROME-P450 27A1;    CEREBROTENDINOUS XANTHOMATOSIS;    CARDIOVASCULAR OUTCOMES;    GLUCOSE-METABOLISM;    INSULIN-RESISTANCE;    INBORN ERROR;    MOUSE MODELS;   

DOI  :  10.3390/cells12101434

来源: SCIE

【 摘 要 】

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.