Hormonal
Overexpression of the mitochondrial deacetylase SIRT3 protects hepatocytes from lipotoxicity by promoting both macroautophagy (lipophagy) and chaperone-mediated autophagy (CMA) through the activation of the AMPK-ULK1 pathway.
This research highlights that maintaining healthy mitochondrial function and NAD+ levels (via exercise, fasting, or metabolic health) may support SIRT3 activity, which in turn helps the liver clear excess fat through autophagy. It suggests that strategies improving metabolic flexibility are more effective than targeting single enzymes in isolation.
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.
Why this rating
The study uses in vitro cell models (AML12 hepatocytes) and in vivo mouse models (HFD-fed mice), but does not include human clinical trials.
Source
SIRT3 promotes lipophagy and chaperon-mediated autophagy to protect hepatocytes against lipotoxicity
Tian Zhang et al. · Cell Death and Differentiation · 2019
DOI 10.1038/s41418-019-0356-z
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