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

Abstract

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 3β-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.

HSDL2 links nutritional cues to bile acid and cholesterol homeostasis

“…It is possible that the incomplete cholesterol breakdown due to HSDL2 depletion may have led to the buildup of cholesterol intermediates in the mitochondria. Numerous studies now show that mitochondrial accumulation of cholesterol and oxysterols impairs mitochondrial function (71,72). Because there are significant differences in the catabolic intermediates produced from cholesterol degradation between immortalized and normal hepatocytes (73)(74)(75), differences in the production and recycling of cholesterol derivates and FXR ligands could have contributed to the alteration of mitochondrial function and FXR activation in these experiments.…”

Integration of Transcriptomics and Lipidomics Profiling to Reveal the Therapeutic Mechanism Underlying Ramulus mori (Sangzhi) Alkaloids for the Treatment of Liver Lipid Metabolic Disturbance in High-Fat-Diet/Streptozotocin-Induced Diabetic Mice

“…Overaccumulated lipids can be oxidized, esterified and restored in the liver, leading to metabolite leakage such as phospholipids, triglycerides, fatty acids and so on [ 57 ]. In order to further explore the regulation of lipid metabolism and inflammation process by SZ-As, an untargeted lipidomics study was performed.…”

Mitochondrial Dysfunction in Metabolic Dysfunction Fatty Liver Disease (MAFLD)

“…Short-chain fatty acids (SCFAs) are a class of saturated and fatty acids produced by intestinal flora through fermentation of soluble dietary fiber, including acetate, propionate, and butyrate. Zhao, T. et al found that butyrate supplementation could inhibit the activity of NADH oxidase in the ETC of MAFLD patients, increase the concentration of potassium ions in the mitochondria, maintain the mitochondrial membrane potential, and delay the development of MAFLD [130,176]. Acetate and propionate mainly maintain the intestinal barrier and reduce the release of inflammatory factors such as IL-6 [177].…”