ArticleGastroenterology2019
Small Heterodimer Partner and Fibroblast Growth Factor 19 Inhibit Expression of NPC1L1 in Mouse Intestine and Cholesterol Absorption.
Article in Gastroenterology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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35 citing papers in PubMed, 58 citations in OpenAlex.
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- FGF-based drug discovery: advances and challenges.Nature reviews. Drug discovery · 2025Review
- Deficiency of Epithelial PIEZO1 Alleviates Liver Steatosis Induced by High-Fat Diet in Mice.International journal of biological sciences · 2025Article
- Bile Acid Signaling in Metabolic and Inflammatory Diseases and Drug Development.Pharmacological reviews · 2024Review
- Bile Acids-Based Therapies for Primary Sclerosing Cholangitis: Current Landscape and Future Developments.Cells · 2024Review
- Zhuyu Pill Alleviates Nonalcoholic Fatty Liver Disease by Regulating Bile Acid Metabolism through the Gut-Liver Axis.ACS omega · 2023Article
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- FXR Signaling-Mediated Bile Acid Metabolism Is Critical for Alleviation of Cholesterol Gallstones byMicrobiology spectrum · 2022Article
- FGF15 promotes hepatic NPC1L1 degradation in lithogenic diet-fed mice.Lipids in health and disease · 2022Article
- Feeding activates FGF15-SHP-TFEB-mediated lipophagy in the gut.The EMBO journal · 2022Article
- Bile acid coordinates microbiota homeostasis and systemic immunometabolism in cardiometabolic diseases.Acta pharmaceutica Sinica. B · 2022Review
- Changes in the intestinal expression of drug metabolism-related genes in a piglet model of parenteral nutrition.Nutrition & metabolism · 2022Article
- Chlorogenic Acid Inhibits Lipid Deposition by Regulating the Enterohepatic FXR-FGF15 Pathway.BioMed research international · 2022Article
- The Nutritional Intervention of Resveratrol Can Effectively Alleviate the Intestinal Inflammation Associated With Celiac Disease Induced by Wheat Gluten.Frontiers in immunology · 2022Article
- Gypenosides Prevent and Dissolve Cholesterol Gallstones by Modulating the Homeostasis of Cholesterol and Bile Acids.Frontiers in medicine · 2022Article
- Gypenosides ameliorate high-fat diet-induced non-alcoholic steatohepatitisFrontiers in nutrition · 2022Article
- Article
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
Abstract
BACKGROUND &
aimsThe nuclear receptor subfamily 0 group B member 2 (NR0B2, also called SHP) is expressed at high levels in the liver and intestine. Postprandial fibroblast growth factor 19 (human FGF19, mouse FGF15) signaling increases the transcriptional activity of SHP. We studied the functions of SHP and FGF19 in the intestines of mice, including their regulation of expression of the cholesterol transporter NPC1L1 )NPC1-like intracellular cholesterol transporter 1) and cholesterol absorption.
methodsWe performed histologic and biochemical analyses of intestinal tissues from C57BL/6 and SHP-knockout mice and performed RNA-sequencing analyses to identify genes regulated by SHP. The effects of fasting and refeeding on intestinal expression of NPC1L1 were examined in C57BL/6, SHP-knockout, and FGF15-knockout mice. Mice were given FGF19 daily for 1 week; fractional cholesterol absorption, cholesterol and bile acid (BA) levels, and composition of BAs were measured. Intestinal organoids were generated from C57BL/6 and SHP-knockout mice, and cholesterol uptake was measured. Luciferase reporter assays were performed with HT29 cells.
resultsWe found that the genes that regulate lipid and ion transport in intestine, including NPC1L1, were up-regulated and that cholesterol absorption was increased in SHP-knockout mice compared with C57BL/6 mice. Expression of NPC1L1 was reduced in C57BL/6 mice after refeeding after fasting but not in SHP-knockout or FGF15-knockout mice. SHP-knockout mice had altered BA composition compared with C57BL/6 mice. FGF19 injection reduced expression of NPC1L1, decreased cholesterol absorption, and increased levels of hydrophilic BAs, including tauro-α- and -β-muricholic acids; these changes were not observed in SHP-knockout mice. SREBF2 (sterol regulatory element binding transcription factor 2), which regulates cholesterol, activated transcription of NPC1L1. FGF19 signaling led to phosphorylation of SHP, which inhibited SREBF2 activity.
conclusionsPostprandial FGF19 and SHP inhibit SREBF2, which leads to repression of intestinal NPC1L1 expression and cholesterol absorption. Strategies to increase FGF19 signaling to activate SHP might be developed for treatment of hypercholesterolemia.
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