Abstract
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-β-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 7α-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.
Highlights
Niemann–Pick C1-like 1 (NPC1L1) is a polytopic transmembrane protein localized at the brush border membrane of the small intestine [1,2]
We and others have shown that NPC1L1 inhibition or deletion protects mice against high-fat diet (HFD)-induced obesity [10,13,14]
It was unknown whether this protection was associated with increased energy expenditure or altered bile acid homeostasis
Summary
Niemann–Pick C1-like 1 (NPC1L1) is a polytopic transmembrane protein localized at the brush border membrane of the small intestine [1,2]. We and others did not detect any significant differences in food or energy intake between L1-KO mice or ezetimibe-treated mice and their respective controls [10,13,14] These observations collectively suggest that mechanisms in addition to intestinal fat absorption may be involved in protecting L1-KO mice from HFD-induced weight gain. Consistent with our hypotheses, we observed that L1-KO mice, compared with their littermate wild-type (WT) controls fed an HFD, had a significant increase in energy expenditure, bile acid pool size, and enrichment of tauro-β-muricholate (TBMC) in the bile acid pool These animals had reduced ileal expression of FGF15, increased hepatic expression of Cyp7A1 and Cyp27A1, and elevated mRNAs levels of TGR5 and Dio in BAT
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