Disruption of Plin5 degradation by CMA causes lipid homeostasis imbalance in NAFLD
- 27 April 2020
- journal article
- research article
- Published by Wiley in Liver International
- Vol. 40 (10), 2427-2438
- https://doi.org/10.1111/liv.14492
Abstract
Background & Aims The pathological hallmark of nonalcoholic fatty liver disease (NAFLD) is an imbalance in hepatic lipid homeostasis, in which lipophagy has been found to play a vital role. However, the underlying molecular mechanisms remain unclear. We investigated the role of chaperone‐mediated autophagy (CMA) in the pathogenesis of NAFLD. Methods CMA activity was evaluated in liver tissues from NAFLD patients and high‐fat diet (HFD)‐fed mice. Liver‐specific LAMP2A‐knockout mice and HepG2 cells lacking LAMP2A [L2A(–) cells] were used to investigate the influence of CMA on lipolysis in hepatocytes. The expression of Plin5, a lipid droplet (LD)‐related protein, was also evaluated in human and mouse liver tissues and in [L2A(–)] cells. Results Here, we found disrupted CMA function in the livers of NAFLD patients and animal models, displaying obvious reduction of LAMP2A and concurrent with decreased levels of CMA positive regulators. More LDs and higher serum triglycerides accumulated in liver‐specific LAMP2A‐knockout mice and L2A(–) cells under high‐fat challenge. Meanwhile, deleting LAMP2A hindered LD breakdown but not increased LD formation. In addition, the LD‐associated protein Plin5 is a CMA substrate, and its degradation through CMA is required for LD breakdown. Conclusions We propose that the disruption of CMA‐induced Plin5 degradation obstacles LD breakdown, explaining the lipid homeostasis imbalance in NAFLD.This publication has 35 references indexed in Scilit:
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