Hepatic COX-2 expression protects mice from an alcohol-high fat diet-induced metabolic disorder by involving protein acetylation related energy metabolism

Abstract

Purpose: A diet high in fat and ethanol often results in chronic metabolic disorder, hepatic steatosis, and liver inflammation. Constitutive hepatic cyclooxygenase-2 (COX-2) expression could protect from high fat-induced metabolism disturbance in a murine model. In this study, we explored the influence of hCOX-2 transgenic [TG] to high fat with ethanol-induced metabolic disorder and liver injury using a mouse animal model.

Methods: 12-week-old male hepatic hCOX-2 transgenic (TG) or wild type mice (WT) were fed either a high fat and ethanol liquid diet (HF+Eth) or a regular control diet (RCD) for 5 weeks (four groups: RCD/WT, RCD/TG; HF+Eth/TG, HF+Eth/WT). We assessed metabolic biomarkers, cytokine profiles, histomorphology, and gene expression to study the impact of persistent hepatic COX-2 expression on diet-induced liver injury.

Results: In the HF+Eth diet, constitutively hepatic human COX-2 expression protects mice from body weight gain and white adipose tissue accumulation, accompanied by improved IPGTT response, serum triglyceride/cholesterol levels, and lower levels of serum and liver inflammatory cytokines. Histologically, hCOX-2 mice showed decreased hepatic lipid droplets accumulation, decreased hepatocyte ballooning, and improved steatosis scores. Hepatic hCOX-2 overexpression enhanced AKT insulin signaling and increased fatty acid synthesis in both RCD and HF+Eth diet groups. The anti-lipogenic effect of hCOX-2 TG in the HF+Eth diet animals was mediated by increasing lipid disposal through enhanced β-oxidation via elevations in the expression of PPARα and PPARγ, and increased hepatic autophagy as assessed by the ratio of autophagy markers LC3 II/I in hepatic tissue. Various protein acetylation pathway components, including HAT, HDAC1, SIRT1, and SNAIL1, were modulated in hCOX-2 TG mice in either RCD or HF+Eth diet.

Conclusions: Hepatic human COX-2 expression protected mice from the metabolic disorder and liver injury induced by a high fat and ethanol diet by enhancing hepatic lipid expenditure. Epigenetic reprogramming of diverse metabolic genes might be involved in the anti-lipogenic effect of COX-2.

Keywords: COX-2; fatty liver disease; metabolism; protein acetylation.