Abstract
Lipophagy is a lysosomal lipolytic pathway that complements the actions of cytosolic neutral lipases. Chaperon-mediated autophagy (CMA) triggers lipid droplets (LDs) breakdown, to initiate lipolysis via either cytosolic lipases or macroautophagy. SIRT3, a mitochondrial NAD+-dependent deacetylase, regulates the acetylation status and activity of many substrates involving in energy metabolism. However, the role of SIRT3 in regulating lipophagy is controversial. The current study showed that SIRT3 expression was decreased and the macroautophagy flux was blocked in the primary hepatocytes from high-fat diet fed mice and P/O (palmitic acid and oleic acid mixture) treated AML12 mouse hepatocytes, compared with the corresponding controls. SIRT3 overexpression promoted macroautophagy in LDs from P/O-treated hepatocytes through activating AMP-activated protein kinase (AMPK) and unc-51-like kinase 1, to boost LDs digestion. Gain of SIRT3 expression stimulated the formation of lysosome-associated membrane protein 2A (LAMP-2A)-heat shock cognate 71 kDa protein (HSC70)-perilipin-2 (PLN2) complex, to promote CMA process and reduce the stability of LDs in hepatocytes. Moreover, SIRT3 reduced the expression of stearoyl-CoA desaturase 1, to suppress lipogenesis. In addition, SIRT3 overexpression promoted LDs dispersion on detyrosinated microtubules, and directly deacetylated long-chain acyl-CoA dehydrogenase to enhance mitochondrial energetics. Taken together, SIRT3 ameliorates lipotoxicity in hepatocytes, which might be a potential target for the treatment of nonalcoholic fatty liver disease.
Highlights
These authors contributed : Tian Zhang, Jingxin LiuEdited by E
We investigated the role of mitochondrial SIRT3 in regulating macroautophagy and Chaperon-mediated autophagy (CMA), as well as modulating lipid droplets (LDs) dispersion, to ameliorate lipotoxicity in hepatocytes, which demonstrated that SIRT3 exerts indispensable role in protecting against Nonalcoholic fatty liver disease (NAFLD)
The current study showed that SIRT3 expression is negatively correlated with lipotoxicity in P/O-treated AML12 hepatocytes and primary hepatocytes from HFD-fed mice
Summary
PLIN2 is the constitutive LDs protein in hepatocytes. PLIN2 abundance is closely associated with the level of intracellular lipid, and PLIN2 protein is highly expressed in the liver from fatty liver patients [8]. Degradation of PLIN2 by CMA is required for the initiation of lipolysis via either cytosolic lipases or macroautophagy, through AMP-activated protein kinase (AMPK)-dependent phosphorylation of PLIN2 [9]. Emerging evidence has indicated that SIRT3 plays an important role in regulating lipid homeostasis and improving NAFLD [14,15,16]. We investigated the role of mitochondrial SIRT3 in regulating macroautophagy and CMA, as well as modulating LDs dispersion, to ameliorate lipotoxicity in hepatocytes, which demonstrated that SIRT3 exerts indispensable role in protecting against NAFLD
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