期刊
CELLS
卷 10, 期 12, 页码 -出版社
MDPI
DOI: 10.3390/cells10123468
关键词
cholesterol; obesity; energy expenditure; TGR5
类别
资金
- National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases [R01DK085176, R01DK111052, R01DK116496, R01DK047987]
- American Diabetes Association [1-18-IBS-346]
- Emory Integrated Lipidomics Core(EILC)
- Georgia Clinical and Translational Science Alliance of the National Institutes of Health
NPC1L1 knockout mice fed a high-fat diet exhibit increased energy expenditure and bile acid pool size, with elevated expression of genes related to energy expenditure in brown adipose tissue, potentially contributing to protection against HFD-induced obesity.
Niemann-Pick C1-like 1 (NPC1L1) mediates intestinal uptake of dietary and biliary cholesterol and is the target of ezetimibe, a cholesterol absorption inhibitor used to treat hypercholesterolemia. Genetic deletion of NPC1L1 or ezetimibe treatment protects mice from high-fat diet (HFD)-induced obesity; however, the molecular mechanisms responsible for this therapeutic benefit remain unknown. A major metabolic fate of cholesterol is its conversion to bile acids. We found that NPC1L1 knockout (L1-KO) mice fed an HFD had increased energy expenditure, bile acid pool size, and fecal bile acid excretion rates. The elevated bile acid pool in the HFD-fed L1-KO mice was enriched with tauro-beta-muricholic acid. These changes in the L1-KO mice were associated with reduced ileal mRNA expression of fibroblast growth factor 15 (FGF15) and increased hepatic mRNA expression of cholesterol 7 alpha-hydroxylase (Cyp7A1) and mitochondrial sterol 27-hydroxylase (Cyp27A1). In addition, mRNA expression of the membrane bile acid receptor Takeda G protein-coupled receptor 5 (TGR5) and type 2 iodothyronine deiodinase (Dio2) were elevated in brown adipose tissue of L1-KO mice, which is known to promote energy expenditure. Thus, altered bile acid homeostasis and signaling may play a role in protecting L1-KO mice against HFD-induced obesity.
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