SIRT3 acts as a positive autophagy regulator to promote lipid mobilization in adipocytes via activating AMPK

Authors: ZANG, TIAN - University Of Macau; LIU, JINGXIN - University Of Macau; TONG, QIANG - Children'S Nutrition Research Center (CNRC); LIN, LIGEN - University Of Macau

Submitted to: International Journal of Molecular Sciences
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/4/2020
Publication Date: 1/7/2020
Citation: Zang, T., Liu, J., Tong, Q., Lin, L. 2020. SIRT3 acts as a positive autophagy regulator to promote lipid mobilization in adipocytes via activating AMPK. International Journal of Molecular Sciences. 21(2):372. https://doi.org/10.3390/ijms21020372.
DOI: https://doi.org/10.3390/ijms21020372

Interpretive Summary: Obesity is an worldwide epidemic, which is characterized by the excessive accumulation of lipids in fat cells. Emerging evidence has demonstrated that autophagy, a cellular self-eating/digestion process, regulates lipid utilization and plays a key role in energy balance. Sirtuin 3 (SIRT3) is a protein modifying enzyme (deacetylase), which is important in regulating autophagy and lipid metabolism. But it is unknown whether SIRT3 modulates autophagy in fat cells. The current study revealed that autophagy was regulated during fat cell formation, which coincided with SIRT3 expression changes in this process. In mature fat cells, overexpression of SIRT3 activated autophagy of lipid droplets, resulting in smaller lipid droplet size and reduced lipid accumulation. SIRT3 overexpression induced the interaction between lipid droplet surface protein perilipin and LAMP2 protein that resides on the surface of lysomes, a structure specialized in the digestion of other cellular component and is invloved in autophagy. In summary, we found SIRT3 is a positive regulator of autophagy to reduce lipid accumulation in fat cells. Therefore, SIRT3 might be a therapeutic target for the treatment of obesity.

Technical Abstract: Obesity is increasing at an alarming rate worldwide, which is characterized by the excessive accumulation of triglycerides in adipocytes. Emerging evidence has demonstrated that macroautophagy and chaperone-mediated autophagy (CMA) regulate lipid mobilization and play a key role in energy balance. Sirtuin 3 (SIRT3) is an NAD+-dependent deacetylase, which is important in regulating macroautophagy and lipid metabolism. It is still unknown whether SIRT3 modulates macroautophagy and CMA in adipocytes. The current study found that macroautophagy was dynamically regulated during 3T3-L1 adipocyte differentiation, which coincided with SIRT3 expression. In mature adipocytes, overexpression of SIRT3 activated macroautophagy, mainly on lipid droplets (LDs), through activating the AMP-activated protein kinase (AMPK)-unc-51-like kinase 1 (ULK1) pathway, which in turn resulting in smaller LD size and reduced lipid accumulation. Moreover, SIRT3 overexpression induced the formation of perilipin-1 (PLN1)-heat shock cognate 71 kDa protein (HSC70)-lysosome-associated membrane protein 2 (LAMP2) complex, to activate CMA and cause the instability of LDs in adipocytes. In summary, we found SIRT3 is a positive regulator of macroautophagy and CMA in adipocytes, which might be a promising therapeutic target for treatment of obesity and its related metabolic dysfunction.