222 - Low level saturated fatty acid palmitate benefits liver cells by boosting mitochondrial homeostasis via CDK1-SIRT3-CPT2 cascade

Abstract

Lipotoxicity-associated diseases such as obesity and cancer are linked to mitochondrial dysfunction due to over digestion of saturated fatty acids (SFAs), especially palmitate (PA) in diet. However, the physiological level of SFAs consumption required for maintaining normal mitochondrial homeostasis and liver functions remains to be elucidated. Here, we demonstrate that, in contrast to the lipotoxic effects induced by high-level PA (HPA), low-level PA (LPA) improves mitochondrial functions which alleviate cellular injuries induced by HPA and CCl4. Mice treated with LPA boost the mitochondrial functions in liver and lessen CCl4-induced hepatotoxicity with improved blood levels of AST, ALT, and m-AST. Restitution of SIRT3 and CPT2 in CRISPR-edited cells demonstrates that LPA-activated mitochondrial function is initiated by SIRT3 that is activated by CDK1 to boost CPT2 activity and fatty acid oxidation. These results provide the evidence for an overlooked advantageous effect of SFAs in mitochondrial homeostasis mediated by a unique CDK1-SIRT3-CPT2 cascade.