White Adipose Tissue Autophagy and Adipose-Liver Crosstalk Exacerbate Nonalcoholic Fatty Liver Disease in Mice

Abstract

Autophagy was enhanced in white adipose tissues of mice fed a high-fat diet. The suppression of autophagy in white adipose tissue ameliorated liver steatosis, inflammation, and fibrosis. Adipocyte autophagy contributes to the liver pathogenesis of nonalcoholic fatty liver disease. BACKGROUND & AIMS:Although nonalcoholic fatty liver disease (NAFLD) is closely associated with obesity, the role of adipose tissue in NAFLD is not well-understood. Because autophagy has been reported to be involved in the degradation of lipid droplets, we investigated the role of adipose tissue autophagy in the liver pathogenesis of NAFLD.METHODS: C57BL/6J mice and adipocyte-specific Atg7knockout mice (Adipoq-Atg7 KO mice) were fed a high-fat diet (HFD).RESULTS: HFD feeding for up to 4 months increased both inguinal and epididymal white adipose tissue (iWAT and eWAT, respectively; the former represents subcutaneous fat, and the latter represents visceral fat) in mice. After HFD feeding, autophagy flux in both types of white adipose tissue was increased, and the levels of Rubicon, a negative autophagy regulator, were decreased, suggesting autophagy promotion.Adipoq-Atg7 KO mice exhibited suppressed autophagy in both iWAT and eWAT. Adipocyte-specific Atg7 KO enhanced HFDinduced iWAT hypertrophy. On the other hand, eWAT levels in Adipoq-Atg7 KO mice were increased after 1 month of HFD feeding but decreased after 4 months of HFD feeding compared with those in wild-type controls. Cleaved caspase 3 and JNK pathway protein expression in eWAT was increased without cytokine elevation in Adipoq-Atg7 KO mice fed an HFD compared with wild-type mice fed an HFD. Adipocyte-specific Atg7 KO decreased serum free fatty acid levels and ameliorated HFD-induced steatosis, liver inflammation, and fibrosis.CONCLUSIONS: Autophagy was enhanced in the white adipose tissues of mice fed an HFD. Autophagy inhibition in white adipose tissues ameliorated the liver pathology of NAFLD via adipose-liver crosstalk.

Docosahexaenoic Acid Attenuates the Progression of Nonalcoholic Steatohepatitis by Suppressing the Adipocyte Inflammation via the G Protein-Coupled Receptor 120/Free Fatty Acid Receptor 4 Pathway

“…Multiple pathways in adipose-liver crosstalk may contribute to the development and progression of NAFLD/NASH [15, 16]. Based on the present findings, we propose a possible mechanism by which excess adipose tissue-derived inflammatory cytokines, induced by CDAHF feeding, enter the liver and damage hepatocytes to induce liver inflammation and fibrosis.…”

“…Increased adipose tissue area is independently associated with NASH or significant fibrosis [14], suggesting that the adipose tissue might be a central target for lifestyle modifications in the patients with NAFLD. Furthermore, a recent study reported that the interaction between the liver and peripheral tissues, mainly adipose tissue, is a key factor in the development of NAFLD [15, 16], indicating a crosstalk between adipose tissue inflammation and NAFLD. This evidence might provide new insights into the putative mechanisms involved in the development of NAFLD.…”

Recent Advances in Adipose Tissue Dysfunction and Its Role in the Pathogenesis of Non-Alcoholic Fatty Liver Disease

“…This implies that approaches targeting BAT to increase thermogenesis and improve BAT functions are also likely to serve the effective management for NAFLD. During obesity, adipose tissue autophagy is increased, and autophagy inhibition ameliorates NAFLD phenotype [ 145 ]. This suggests that therapeutic agents that inhibit WAT autophagy is viable for managing NAFLD.…”

Crossing the Rubicon: Adipose Tissue Autophagy Breaks Out NAFLD

“…In the current issue of Cellular and Molecular Gastroenterology and Hepatology , Sakane et al 3 provide a novel mechanism of adipose tissue autophagy-mediated NAFLD progression. The authors first show that changes in adipose tissue autophagy following high-fat diet feeding are associated with the pathogenesis of NAFLD.…”

“…Sakane et al 3 further investigated the role of adipose tissue autophagy on the NAFLD pathogenesis using adipocyte-specific Atg7-null (Adipoq-Atg7 null) mice. Atg7 plays a central role in autophagosome formation, and its deficiency causes a decrease in autophagy activity, mediating intracellular fat accumulation.…”