Molecular pathways of nonalcoholic fatty liver disease development and progression

Oct 22, 2018Cellular and molecular life sciences : CMLS

Molecular processes involved in the development and worsening of nonalcoholic fatty liver disease

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Abstract

Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver conditions, from simple fat accumulation to severe liver damage.

NAFLD is associated with metabolic syndrome and can progress to more severe forms like nonalcoholic steatohepatitis (NASH) and cirrhosis.
The initial development of NAFLD may be triggered by the accumulation of toxic free fatty acids due to insulin resistance.
Progression of the disease involves multiple injury mechanisms, including oxidative stress and inflammation.
Key features of NASH include inflammation, cell death, and fibrosis, which are linked to various stressors and signaling pathways.
Understanding molecular mechanisms is crucial for identifying factors that influence the onset and progression of NAFLD.

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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.

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Molecular pathways of nonalcoholic fatty liver disease development and progression

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