Expressing the Human Cholesteryl Ester Transfer Protein Minigene Improves Diet-Induced Fatty Liver and Insulin Resistance in Female Mice.

Lin Zhu,Thao Luu,Charles R Flynn,Julia An,Sivaprakasam Chinnarasu,Hye-Young H Kim,Macrae F Linton,Bridget Litts,Yasminye D Pettway,Kelly Fahey,John M Stafford

doi:10.3389/fphys.2021.799096

Lin Zhu, Thao Luu + Show 9 more

Open Access

https://doi.org/10.3389/fphys.2021.799096

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Abstract

Mounting evidence has shown that CETP has important physiological roles in adapting to chronic nutrient excess, specifically, to protect against diet-induced insulin resistance. However, the underlying mechanisms for the protective roles of CETP in metabolism are not yet clear. Mice naturally lack CETP expression. We used transgenic mice with a human CETP minigene (huCETP) controlled by its natural flanking region to further understand CETP-related physiology in response to obesity. Female huCETP mice and their wild-type littermates were fed a high-fat diet for 6 months. Blood lipid profile and liver lipid metabolism were studied. Insulin sensitivity was analyzed with euglycemic-hyperinsulinemic clamp studies combined with 3H-glucose tracer techniques. While high-fat diet feeding induced obesity for huCETP mice and their wild-type littermates lacking CETP expression, insulin sensitivity was higher for female huCETP mice than for their wild-type littermates. There was no difference in insulin sensitivity for male huCETP mice vs. littermates. The increased insulin sensitivity in females was largely caused by the better insulin-mediated suppression of hepatic glucose production. In huCETP females, CETP in the circulation decreased HDL-cholesterol content and increased liver cholesterol uptake and liver cholesterol and oxysterol contents, which was associated with the upregulation of LXR target genes in long-chain polyunsaturated fatty acid biosynthesis and PPARα target genes in fatty acid β-oxidation in the liver. The upregulated fatty acid β-oxidation may account for the improved fatty liver and liver insulin action in female huCETP mice. This study provides further evidence that CETP has beneficial physiological roles in the metabolic adaptation to nutrient excess by promoting liver fatty acid oxidation and hepatic insulin sensitivity, particularly for females.

Highlights

In humans, cholesteryl ester transfer protein (CETP) shuttles cholesteryl esters from high-density lipoprotein (HDL) to apoB-containing particles (VLDL and low-density lipoprotein (LDL)) and transfers triglycerides (TG) from apoB-containing particles into HDL in the circulation
We show that female transgenic mice expressing the human CETP minigene containing its natural regulatory elements are protected from diet-induced insulin resistance
Expression of the human CETP minigene increased liver longchain polyunsaturated fatty acid (LC-PUFA) levels and stimulated hepatic fatty acid β-oxidation pathways, which is likely responsible for the limited liver TG content and improved whole-body insulin sensitivity during high-fat diet feeding

Summary

Introduction

Cholesteryl ester transfer protein (CETP) shuttles cholesteryl esters from HDL to apoB-containing particles (VLDL and LDL) and transfers triglycerides (TG) from apoB-containing particles into HDL in the circulation. CETP inhibition has been pursued as an approach to increase HDL-cholesterol levels and reduce CVD risk. Most clinical trials have not shown that CETP inhibition reduces CVD risk (Barter et al, 2007; Kastelein et al, 2007; Lincoff et al, 2017), anacetrapib had modest CVD risk reduction after 4 years of follow-up (Group et al, 2017). Clinical studies have shown that the association between blood CETP levels and CVD risk depends on plasma TG levels and sex (Boekholdt et al, 2004; Robins et al, 2013). Obesity and hyperlipidemia are known to significantly impact aspects of cholesterol metabolism and HDL biology and may impact aspects of CETP-mediated biology (Cappel et al, 2013; Palmisano et al, 2016; Zhu et al, 2018a; van den Boogert et al, 2020)

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