SIRT3 promotes lipophagy and chaperon-mediated autophagy to protect hepatocytes against lipotoxicity

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.

Corilagin Alleviates Nonalcoholic Fatty Liver Disease in High-Fat Diet-Induced C57BL/6 Mice by Ameliorating Oxidative Stress and Restoring Autophagic Flux

“…effects of FFAs on autophagic flux using human nontumor hepatic cell line L02 cells (human hepatic L02 cells) and found that autophagic flux was blocked at the late hour (24,36 h) of steatosis due to homeostatic imbalance Kim et al, 2018;Zhang et al, 2019).Likewise, our results were further confirmed in vitro experiments ( Figure 4B). In particular, combined treatment with autophagy inhibitor (3-MA) evidently inhibited Cori-mediated decrease of p62 protein levels ( Figure 4B).…”

SIRT3 Acts as a Positive Autophagy Regulator to Promote Lipid Mobilization in Adipocytes via Activating AMPK

“…The OCR was determine by using a Seahorse Bioscience XF24-3 Extracellular Flux Analyzer (Agilent, Santa Clara, CA, USA), as described previously [26]. 3T3-L1 cells were seeded in XF24-well microplates (Seahorse Bioscience, Billerica, MA, USA) at 5 × 10 5 cells per well.…”

“…Sirt3 deficiency inhibits macroautophagy and disrupts mitochondrial homeostasis in cardiac aging mice [24,25]. Overexpression of Sirt3 induces macroautophagy and CMA to protect against lipotoxicity in hepatocytes [26]. Sirt3 overexpression activates macroautophagy to prevent mitochondrial injury and cardiomyocyte apoptosis [27].…”

Sirtuin 3 governs autophagy‐dependent glycolysis during Angiotensin II‐induced endothelial‐to‐mesenchymal transition

“…SIRT3 also acts as a positive regulator of autophagy via its deacetylation of crucial autophagic proteins. [17][18][19] Our previous study revealed that ablation of SIRT3 directly impairs EC-associated autophagy, resulting in severe microvascular rarefaction. Moreover, several groups have found that the loss of SIRT3 causes a shift toward glycolytic metabolism.…”