Disruption of Plin5 degradation by CMA causes lipid homeostasis imbalance in NAFLD

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 highfat 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.

The Role of Lipophagy in the Development and Treatment of Non-Alcoholic Fatty Liver Disease

“…Further in vitro experiments revealed that LAMP3 overexpression resulted in higher expression of lipogenic genes. More evidence for a link between LAMP and NAFLD was demonstrated in livers of 24 NAFLD patients with varying degrees of steatosis (mild, moderate, severe) where a reduction of LAMP2A expression and other positive regulators of autophagy such as PLIN5 was found ( 92 ).…”

Understanding the Role of Perilipin 5 in Non-Alcoholic Fatty Liver Disease and Its Role in Hepatocellular Carcinoma: A Review of Novel Insights

“…As mentioned before, NAFLD is characterized by increased accumulation of LD in the liver as well as increased expression of PLIN5 [ 12 ]. This has been previously reported in patients with severe NAFLD as well as in mice fed with a high fat diet (HFD) inducing NAFLD [ 12 , 23 ].…”

“…As mentioned before, NAFLD is characterized by increased accumulation of LD in the liver as well as increased expression of PLIN5 [ 12 ]. This has been previously reported in patients with severe NAFLD as well as in mice fed with a high fat diet (HFD) inducing NAFLD [ 12 , 23 ]. Interestingly, compared to PLIN5 protein levels, mRNA levels are only slightly increased, suggesting that elevated PLIN5 activity is regulated post-transcriptionally [ 12 ].…”

“…NAFLD is characterized by augmented accumulation of hepatic LD, which is in line with increased PLIN5 expression [ 12 ]. Recently, alterations in lipid metabolism have also been proposed as a new hallmark of cancer [ 13 , 14 , 15 ].…”

“…Moreover, several cellular processes such as oxidative stress, ER stress, and inflammation have been related to non-alcoholic steatohepatitis (NASH) the progressed form of NAFLD [ 16 , 17 ] as well as to cancer development and progression [ 18 , 19 ]. Meanwhile, PLIN5 has indeed been implicated in the regulation of lipid and glucose homeostasis and many cellular processes such as oxidative stress, ER stress, inflammation, and autophagy [ 12 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ]. This evidence once again supports the notion that PLIN5 could play a direct role in transition from NAFLD to HCC.…”