Nonalcoholic Fatty liver disease: pathogenesis and therapeutics from a mitochondria-centric perspective.

Aaron M Gusdon,Shen Qu,Ke-Xiu Song

doi:10.1155/2014/637027

Abstract

Nonalcoholic fatty liver disease (NAFLD) describes a spectrum of disorders characterized by the accumulation of triglycerides within the liver. The global prevalence of NAFLD has been increasing as the obesity epidemic shows no sign of relenting. Mitochondria play a central role in hepatic lipid metabolism and also are affected by upstream signaling pathways involved in hepatic metabolism. This review will focus on the role of mitochondria in the pathophysiology of NAFLD and touch on some of the therapeutic approaches targeting mitochondria as well as metabolically important signaling pathways. Mitochondria are able to adapt to lipid accumulation in hepatocytes by increasing rates of beta-oxidation; however increased substrate delivery to the mitochondrial electron transport chain (ETC) leads to increased reactive oxygen species (ROS) production and eventually ETC dysfunction. Decreased ETC function combined with increased rates of fatty acid beta-oxidation leads to the accumulation of incomplete products of beta-oxidation, which combined with increased levels of ROS contribute to insulin resistance. Several related signaling pathways, nuclear receptors, and transcription factors also regulate hepatic lipid metabolism, many of which are redox sensitive and regulated by ROS.

Highlights

Nonalcoholic fatty liver disease (NAFLD) is a broad term used to encompass a range of disorders ranging in severity from excess triglyceride accumulation in the liver to hepatic steatosis and eventually fibrosis, cirrhosis, and hepatocellular carcinoma
Vitamin E therapy is only recommended in nondiabetic NAFLD patients with biopsy proven nonalcoholic steatohepatitis (NASH) [87]
While many of the molecular mechanisms involved in the pathogenesis of NAFLD are still being worked out, mitochondria lie at the core of NAFLD

Summary

Introduction

NAFLD is a broad term used to encompass a range of disorders ranging in severity from excess triglyceride accumulation in the liver to hepatic steatosis and eventually fibrosis, cirrhosis, and hepatocellular carcinoma. Hepatic lipid accumulation results from a combination of uptake from circulating free fatty acids (FFAs), de novo lipogenesis, and dietary fats [2]. This lipid accumulation leads to hepatic steatosis, which is characterized by the accumulation of triglycerides (TGs) as lipid droplets within hepatocytes [3]. Increased carbohydrate metabolism leads to increased abundance of acetyl-coenzyme A (acetyl-CoA), which can be used as a substrate for lipogenesis. Both insulin and glucose activate signaling pathways leading to lipogenesis. This review will focus on alterations in mitochondrial function as well as the upstream signaling pathways which converge on the mitochondria and their role in the pathogenesis of NAFLD and implications for treatment

The Role of Mitochondria in the Etiology of NAFLD

Insulin Resistance

Signaling Pathways and Nuclear Receptors

Findings

Conclusions