Journal Article

Molecular pathways of nonalcoholic fatty liver disease development and progression

Razori, María Valeria, Bessone, Fernando, Roma, Marcelo G

2019

Overview

Nonalcoholic fatty liver disease (NAFLD) is a main hepatic manifestation of metabolic syndrome. It represents a wide spectrum of histopathological abnormalities ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) with or without fibrosis and, eventually, cirrhosis and hepatocellular carcinoma. While hepatic simple steatosis seems to be a rather benign manifestation of hepatic triglyceride accumulation, the buildup of highly toxic free fatty acids associated with insulin resistance-induced massive free fatty acid mobilization from adipose tissue and the increased de novo hepatic fatty acid synthesis from glucose acts as the “first hit” for NAFLD development. NAFLD progression seems to involve the occurrence of “parallel, multiple-hit” injuries, such as oxidative stress-induced mitochondrial dysfunction, endoplasmic reticulum stress, endotoxin-induced, TLR4-dependent release of inflammatory cytokines, and iron overload, among many others. These deleterious factors are responsible for the triggering of a number of signaling cascades leading to inflammation, cell death, and fibrosis, the hallmarks of NASH. This review is aimed at integrating the overwhelming progress made in the characterization of the physiopathological mechanisms of NAFLD at a molecular level, to better understand the factor influencing the initiation and progression of the disease.

• Publisher: Springer Nature B.V
• Subject: Abnormalities / Acid resistance / Adipose tissue / Cascades / Cell death / Cirrhosis / Cytokines / Endoplasmic reticulum / Endotoxins / Fatty acids / Fatty liver / Fibrosis / Hepatocellular carcinoma / Inflammation / Insulin / Liver / Liver cancer / Liver cirrhosis / Liver diseases / Metabolic disorders / Metabolic syndrome / Mitochondria / Oxidative stress / Steatosis / TLR4 protein / Toll-like receptors