Lipogenesis and lipolysis largely determining adipose tissues and liver lipid content, and the imbalance between them contributes to fatty liver disease and metabolic syndromes. Lipogenesis and lipolysis are regulated by nutritional signals and metabolic hormones such as insulin through multiple mechanisms. Apolipoprotein A-IV (ApoA4), secreted largely by intestine, is existed as the composition of HDL and as the free form mostly in blood. ApoA4 plays the important roles in anti-atherosclerosis and lowering blood glucose. After we found its suppressing hepatic gluconeogenesis via NR1D1/NR4A1, and promoting glucose uptake in adipose tissues through PI3K-Akt-GLUT4, we have studied the action of ApoA4 on lipid metabolism with ApoA4 knock-out mice (A4KO). We found that ApoA4 deficiency resulted in worse fatty liver in diet induced obesity (DIO) mice. ApoA4 deficiency lowered the expression of hepatic ATGL, the rate-limiting enzyme for lipolysis, but enhanced the expression of key lipogenic enzymes such as ACC and SCD1. However, the expression of ATGL was increased and the expression of ACC, SCD1, FAS as well as their transcriptional activator SREBP1 were decreased from both BAT and WAT in A4KO mice. Furthermore, ApoA4 deletion also resulted in the inhibited expression of key proteins in thermogenesis pathway SIRT1, PGC1 and UCP1. Moreover, either overexpression of ApoA4 by delivery of AAV-ApoA4 or one time injection of ApoA4 protein resulted in reversed expression of key enzymes for lipogenesis and lipolysis both in liver and adipose tissues from A4KO DIO mice. These data suggest that ApoA4 may promote lipolysis in liver, but inhibited lipolysis and enhance lipogenesis and energy metabolism in adipose tissues, implying ApoA4’s action of regulating the trafficking of lipids from liver to fat and then turn fat into energy for burning.
X. Li: None. X. Liu: None. C. Cheng: None. J. Zhou: None. J. Fan: None. S. Li: None.
National Natural Science Foundation of China (81770798, 81700691)