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 PPARa and PPARg, 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.
Highlights
We have investigated fat metabolism in COX-2 TG or wild type (WT) mice under a high fat with ethanol diet, revealing that COX-2 TG mice are protected from diet-induced weight gain, metabolic syndrome, and liver damage
We have investigated nutritional metabolism in WT and COX-2 TG mice on RCD or HFþEth diet for 5 weeks
Our results indicated that COX-2TG mice were protected from nutritional stress-induced obesity, insulin resistance, and liver damage
Summary
Holcomb, & Nunez, 2010; Srinivasan, Shawky, Kaphalia, Thangaraju, & Segar, 2019; Traversy & Chaput, 2015).In animal models, it has been demonstrated that ethanol exaggerates liver inflammation, while it has been shown that, according to the frequency of consumption, ethanol could partially protect mice/rats from high fat diet-induced insulin resistance and obesity (Chang et al, 2015;Coker et al, 2020;Demori, Voci, Fugassa, & Burlando, 2006;Feng et al, 2012;Lindtner et al, 2013;Wang, Seitz, & Wang, 2010).Emerging evidence suggests a critical role for cyclooxygenase-2 (COX-2) in the link between inflammation and nutrition metabolism. It has been reported that hepatic COX-2 transgenic mice are protected from streptozotocin (STZ) or high fat-induced hyperglycemia, insulin resistance, and liver damage (Carboneau, Breyer, & Gannon, 2017; Motin~o et al, 2019). It has been well documented that COX-2 TG mice are protected from HF-induced hepatic steatosis, weight gain, and insulin resistance, but ethanol's effect on a high fat diet in nutrition metabolism and liver injury has not been explored. We theorize that protein acetylation is one underlying mechanism that regulates metabolism-related gene expression epigenetically, and further mediates the protective function of hepatic COX-2 overexpression
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