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Publication
Expressing the Human Cholesteryl Ester Transfer Protein Minigene Improves
Diet-Induced Fatty Liver and Insulin Resistance in Female Mice.
Authors Zhu L, An J, Chinnarasu S, Luu T, Pettway YD, Fahey K, Litts B, Kim HH, Flynn
CR, Linton MF, Stafford JM
Submitted By Submitted Externally on 3/9/2022
Status Published
Journal Frontiers in physiology
Year 2021
Date Published
Volume : Pages 12 : 799096
PubMed Reference 35082691
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 PPARa target genes in fatty acid
ß-oxidation in the liver. The upregulated fatty acid ß-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.




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