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

Cell Death Differ. 2020 Jan;27(1):329-344. doi: 10.1038/s41418-019-0356-z. Epub 2019 Jun 3.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy-Related Protein-1 Homolog / metabolism
  • Cell Line
  • Chaperone-Mediated Autophagy*
  • Diet, High-Fat
  • Hepatocytes / enzymology
  • Hepatocytes / metabolism*
  • Lipid Droplets / metabolism
  • Lipid Metabolism
  • Lipolysis*
  • Macroautophagy*
  • Male
  • Mice, Inbred C57BL
  • Microtubules / metabolism
  • Mitochondria / metabolism
  • Protein Kinases / metabolism
  • Sirtuin 3 / metabolism
  • Sirtuin 3 / physiology*
  • Stearoyl-CoA Desaturase / metabolism

Substances

  • Sirt3 protein, mouse
  • Scd1 protein, mouse
  • Stearoyl-CoA Desaturase
  • Protein Kinases
  • AMP-activated protein kinase kinase
  • Autophagy-Related Protein-1 Homolog
  • Ulk1 protein, mouse
  • Sirtuin 3