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ARS Home » Plains Area » Houston, Texas » Children's Nutrition Research Center » Research » Publications at this Location » Publication #365694
Title: SIRT3 promotes lipophagy and chaperon-mediated autophagy to protect hepatocytes against lipotoxicity

Author
item ZHANG, TIAN - UNIVERSITY OF MACAU
item LIU, JINGXIN - UNIVERSITY OF MACAU
item SHEN, SHENGNAN - UNIVERSITY OF MACAU
item TONG, QIANG - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC)
item MA, XIAOJUN - ZHENGZHOU UNIVERSITY
item LIN, LIGEN - UNIVERSITY OF MACAU

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

Interpretive Summary: Lysosome is the garbage disposal structure inside a cell. Lipophagy is the process that a lysosome digest lipids inside a cell. The current study showed that SIRT3 expression was decreased and the lipophagy was blocked in the liver cells from high-fat diet fed mice or lipid-treated cultured liver cells. Elevating SIRT3 level promoted lipophagy to boost the digestion of lipid droplet inside liver cells. SIRT3 stimulated the assembly of proteins involved in lipophagy to reduce the stability of lipid droplets and facilitate their digestion. In addition, SIRT3 regulated long-chain acyl-CoA dehydrogenase, a key enzyme for lipid breakdown, to enhance fat burning. Moreover, SIRT3 also suppressed lipid synthesis by reduced the expression of SCA1, an enzyme involved in lipid synthesis. Taken together, SIRT3 increases lipid digestion and utilization and decreases lipid synthesis to ameliorate lipid toxicity in liver cells. Therefore, SIRT3 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 71kDa 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.