New Aspects of Lipotoxicity in Nonalcoholic Steatohepatitis

Abstract

NASH is becoming increasingly common worldwide because of the growing global prevalence of obesity and consequently NAFLD. Unfortunately, the mechanism of progression of NAFLD to NASH and then cirrhosis is not completely understood. Several factors, including insulin resistance, inflammation, oxidative stress, lipotoxicity, and bile acid (BA) toxicity, have been reported to be associated with NASH progression. The release of fatty acids from dysfunctional and insulin-resistant adipocytes results in lipotoxicity, which is caused by the ectopic accumulation of triglyceride-derived toxic metabolites and the subsequent activation of inflammatory pathways, cellular dysfunction, and lipoapoptosis. Adipose tissue (AT), especially visceral AT, comprises multiple cell populations that produce adipokines and insulin-like growth factor, plus macrophages and other immune cells that stimulate the development of lipotoxic liver disease. These biomolecules have been recently linked with many digestive diseases and gastrointestinal malignancies such as hepatocellular carcinoma. This made us question what role lipotoxicity has in the natural history of liver fibrosis. Therefore, this review focuses on the close relationship between AT and NASH. A good comprehension of the pathways that are related to dysregulated AT, metabolic dysfunction, and hepatic lipotoxicity will result in the development of prevention strategies and promising therapeutics for patients with NASH.

Dual Specificity Phosphatase 12 Regulates Hepatic Lipid Metabolism Through Inhibition of the Lipogenesis and Apoptosis Signal–Regulating Kinase 1 Pathways

“…NAFLD is characterized by an accumulation of intrahepatic lipids. Lipotoxicity is emerging when the hepatic capability to use, store, and output free fatty acids as triglycerides is surpassed by free fatty acid flux or liver de novo lipogenesis, thus triggering hepatocyte death, inflammation, and fibrosis . Interestingly, our study demonstrates that the liver sections of DUSP12‐CKO mice fed an HFD exhibited a remarkable increase in lipid accumulation as evidenced by staining with H&E and oil red O.…”

Anti-NASH Drug Development Hitches a Lift on PPAR Agonism

“…Nutritional habits are often uniformly classified as a major cause of the metabolic syndrome and obesity. Nevertheless, different carbohydrates and lipid species can govern and drive divergent metabolic processes [94,95]. However, this is often neglected in the development of novel drugs against diseases with heterogeneous pathogeneses.…”

Effects of walnut oil on metabolic profile and transcription factors in rats fed high‐carbohydrate‐/‐fat diets

“…glucotoxicity (Mendez-Sanchez et al, 2018;Mota, Banini, Cazanave, & Sanyal, 2016). It is known that the obese individuals are more prone to fatty liver diseases, and metabolic syndrome which was also reported to arise from the factors such as excessive intake of simple carbohydrates and fat gain via the consumption of high fat (HFD) and high carbohydrate diets (HCD) (Fernando, Chin, Ton, & Abdul Kadir, 2013;Molinar-Toribio et al, 2018;.…”