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

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.

Chromosome-level genome and population genomics reveal evolutionary characteristics and conservation status of Chinese indigenous geese

“…Involved genes such as APOB participate in de novo synthesis of fatty acids and were associated with goose hepatic steatosis 38 . Cholesteryl ester transfer protein ( CETP ) has been shown to play a role in liver lipid metabolism 39 . Translocator protein ( TSPO ) regulates steatosis in nonalcoholic fatty liver disease 40 .…”

Association between the use of lipid‐lowering drugs and the risk of inflammatory bowel disease

“…Proprotein convertase subtilisin‐kexin type 9 (PCSK9) can bind to the LDL receptor, mediate the degradation of the receptor and affect the clearance of cholesterol 13 . Cholesteryl ester transfer protein (CETP) mediates the transport of cholesterol from high‐density lipoprotein to very‐low‐density lipoprotein and low‐density lipoprotein (LDL) and plays a role in liver lipid metabolism 14 . Apolipoprotein B (APOB) is involved in the lipid transport process and is the main protein of LDL.…”

“…13 Cholesteryl ester transfer protein (CETP) mediates the transport of cholesterol from high-density lipoprotein to very-low-density lipoprotein and low-density lipoprotein (LDL) and plays a role in liver lipid metabolism. 14 Apolipoprotein B (APOB) is involved in the lipid transport process and is the main protein of LDL. Among them, statins are commonly used lipid-lowering drugs that primarily reduce cholesterol synthesis by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase.…”

Supplementation of Silymarin Alone or in Combination with Salvianolic Acids B and Puerarin Regulates Gut Microbiota and Its Metabolism to Improve High-Fat Diet-Induced NAFLD in Mice

“…In this study, both the MSL and HSL groups showed improvements in insulin levels, yet the HDL-C levels in mice from these groups, as well as the PD group, decreased, which seems inconsistent with the aforementioned research. However, some studies have found that increases in HDL-C levels may also be accompanied by hepatic lipid accumulation and worsening insulin resistance [ 56 , 57 ]. Interestingly, following intervention with certain phytochemicals in mice, both increased HDL-C levels and improvements in insulin resistance have been observed [ 58 , 59 ].…”