NPC1L1 Deficiency Suppresses Ileal Fibroblast Growth Factor 15 Expression and Increases Bile Acid Pool Size in High-Fat-Diet-Fed Mice
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 obesit...
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MDPI AG
2021-12-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/10/12/3468 |
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| author | Lin Jia Yinyan Ma Jamie Haywood Long Jiang Bingzhong Xue Hang Shi Paul A. Dawson Liqing Yu |
| author_facet | Lin Jia Yinyan Ma Jamie Haywood Long Jiang Bingzhong Xue Hang Shi Paul A. Dawson Liqing Yu |
| author_sort | Lin Jia |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T04:25:40Z |
| format | Article |
| id | doaj.art-4fafef83412742538ce8897a2e0d1533 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T04:25:40Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-4fafef83412742538ce8897a2e0d15332023-11-23T07:38:13ZengMDPI AGCells2073-44092021-12-011012346810.3390/cells10123468NPC1L1 Deficiency Suppresses Ileal Fibroblast Growth Factor 15 Expression and Increases Bile Acid Pool Size in High-Fat-Diet-Fed MiceLin Jia0Yinyan Ma1Jamie Haywood2Long Jiang3Bingzhong Xue4Hang Shi5Paul A. Dawson6Liqing Yu7Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USADepartment of Pathology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USADepartment of Pathology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USADivision of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USADepartment of Endocrinology and Metabolism, Wake Forest School of Medicine, Winston-Salem, NC 27157, USADepartment of Biology, Georgia State University, Atlanta, GA 30303, USADepartment of Pathology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USADepartment of Pathology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USANiemann–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.https://www.mdpi.com/2073-4409/10/12/3468NPC1L1cholesterolobesityenergy expenditureTGR5 |
| spellingShingle | Lin Jia Yinyan Ma Jamie Haywood Long Jiang Bingzhong Xue Hang Shi Paul A. Dawson Liqing Yu NPC1L1 Deficiency Suppresses Ileal Fibroblast Growth Factor 15 Expression and Increases Bile Acid Pool Size in High-Fat-Diet-Fed Mice Cells NPC1L1 cholesterol obesity energy expenditure TGR5 |
| title | NPC1L1 Deficiency Suppresses Ileal Fibroblast Growth Factor 15 Expression and Increases Bile Acid Pool Size in High-Fat-Diet-Fed Mice |
| title_full | NPC1L1 Deficiency Suppresses Ileal Fibroblast Growth Factor 15 Expression and Increases Bile Acid Pool Size in High-Fat-Diet-Fed Mice |
| title_fullStr | NPC1L1 Deficiency Suppresses Ileal Fibroblast Growth Factor 15 Expression and Increases Bile Acid Pool Size in High-Fat-Diet-Fed Mice |
| title_full_unstemmed | NPC1L1 Deficiency Suppresses Ileal Fibroblast Growth Factor 15 Expression and Increases Bile Acid Pool Size in High-Fat-Diet-Fed Mice |
| title_short | NPC1L1 Deficiency Suppresses Ileal Fibroblast Growth Factor 15 Expression and Increases Bile Acid Pool Size in High-Fat-Diet-Fed Mice |
| title_sort | npc1l1 deficiency suppresses ileal fibroblast growth factor 15 expression and increases bile acid pool size in high fat diet fed mice |
| topic | NPC1L1 cholesterol obesity energy expenditure TGR5 |
| url | https://www.mdpi.com/2073-4409/10/12/3468 |
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