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

Authors: ZHANG, TIAN - University Of Macau; LIU, JINGXIN - University Of Macau; SHEN, SHENGNAN - University Of Macau; TONG, QIANG - Children'S Nutrition Research Center (CNRC); MA, XIAOJUN - Zhengzhou University; LIN, LIGAN - University Of Macau

Submitted to: Cell Death and Differentiation
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/15/2019
Publication Date: 1/5/2020
Citation: Zhang, T., Liu, J., Shen, S., Tong, Q., Ma, X., Lin, L. 2020. SIRT3 promotes lipophagy and chaperon-mediated autophagy to protect hepatocytes against lipotoxicity. Cell Death and Differentiation. 27:329-344. https://doi.org/10.1038/s41418-019-0356-z.
DOI: https://doi.org/10.1038/s41418-019-0356-z

Interpretive Summary: Autophagy is a cellular process of self-digesting of various cellular components, whereas lipophagy is one type of autophagy of the digesting of cellular lipids. SIRT3 is a protein modifying enzyme (deacetylase) residuing in the power plant of cells called mitochondrial. The current study showed that SIRT3 amount was decreased and autophagy process was blocked in isolated liver cells from high-fat diet fed mice or fatty acid mixture treated cultured mouse liver cells. Increasing SIRT3 levels can promote autophagy in liver cells through activating two singlaing proteins, AMPK and ULK1, to boost cellular lipid digestion. Moreover, SIRT3 reduced the expression of stearoyl-CoA desaturase 1, an enzyme involved in lipid synthesis, to suppress lipid formation. In addition, SIRT3 overexpression promoted the breakdown and burning of lipids to provide energy for these processes. Taken together, SIRT3 ameliorates lipid toxicity in liver cells, which might be a potential target for the treatment of fatty liver disease.

Technical 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.