Roles of Chemerin Knockout in Aerobic Exercise-Induced Improvement of Nonalcoholic Fatty Liver in High Fat Diet Mice and Its Mechanisms

This study was to investigate the roles of adipokine chemerin in regulating NAFLD (nonalcoholic fatty liver disease) in mice fed with high fat diet at basic and motor states using two kinds of chemerin knockout mice, adipose specific-chemerin knockout (adipo-chemerin–/–) mice and global chemerin knockout (chemerin–/–) mice. Cre-loxp system were employed to generate adipo-chemerin–/– and chemerin–/– mice. Then male wild-type (WT) mice, adipo-chemerin–/– mice and chemerin–/– mice were undertaken diet intervention, fed with 12-week ND (normal diet) or HFD (high-fat diet). In addition, 6-week HFD feeding mice of the above three groups adopted 6-week moderate intensity running intervention, composing WT+E, adipo-chemerin–/–+E and chemerin–/–+E groups. The body weight, liver weight, serum ALT (alanine aminotransferase) and AST (aspartate aminotransferase), blood lipid, liver gross specimen and histopathological analysis, and the protein levels of multiple liver lipid metabolism enzymes and key proteins such as CD36 (cluster of differentiation 36), PPARα (peroxisome proliferator-activated receptor α), CPT1 (carnitine palmitoyltransferase 1), SREBP-1 (sterol regulatory element binding protein 1) and SCD1 (stearoyl coenzyme A desaturase 1) were determined. The results show that (1) compared with WT mice fed with ND, HFD feeding WT mice had NAFLD, represented as heavier liver weight, higher serum ALT and AST contents, dyslipidemia, and large, yellow and oil liver as well as increases of lipid droplets and fat vacuole area under the microscope (P<0.05); (2) in HFD+adipo-chemerin–/– mice, compared with HFD+WT mice, the obesity rate was decreased and NAFLD was improved, while the opposite results were found in HFD+chemerin–/– including increased obesity rate and worsen NAFLD (P<0.05). As for the mechanisms, the protein levels of CD36, SREBP-1 and SCD1 were down-regulated and CPT1 were up-regulated in adipo-chemerin–/– mice (P<0.05). On the contrary, the protein levels of CD36 and SREBP-1 were up-regulated in chemerin –/– mice. (3) Adipo-specific chemerin knockout further enhanced the improving effect of exercise on NAFLD and the lipid metabolism enzymes, reflected as the decrease of TC content, the increase of liver CPT1, and the further decreases of liver CD36 and SCD1. While global chemerin knockout attenuated exercise-induced improvements in NAFLD and the lipid metabolism enzymes, including the disappears of exercise-induced regulations on serum TG and LDL as well as on liver SREBP-1, SCD1 and CPT1, and the attenuation of exercise-induced decrease of AST (P<0.05). The study concluded that adipo-specific chemerin knockout improved NAFLD of male HFD mice and enhanced the improving effect of exercise on NAFLD while global chemerin knockout aggravated NAFLD and weakened the improving effect of exercise, which were likely to be related to the promotion and inhibition on liver multiple lipid metabolism key enzymes and protein induced by chemerin decrease (adipo-specific chemerin knockout) and chemerin deficiency (global chemerin knockout), respectively.

CSTR: 32200.14.cjcb.2023.10.0003