ArticleThe Journal of biological chemistry2012
Activation of the farnesoid X receptor induces hepatic expression and secretion of fibroblast growth factor 21.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 82 papers, 1 of them a synthesis that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
82 citing papers in PubMed, 1 synthesis or guideline pooled it, 154 citations in OpenAlex.
- The Influence of Bariatric Surgery on Serum Bile Acids in Humans and Potential Metabolic and Hormonal Implications: a Systematic Review.Current obesity reports · 2015Pooled it
- Trial
- A randomised, double-blind, placebo-controlled phase 1 study of the safety, tolerability and pharmacodynamics of volixibat in overweight and obese but otherwise healthy adults: implications for treatment of non-alcoholic steatohepatitis.BMC pharmacology & toxicology · 2018Trial
- Safety, tolerability and pharmacodynamics of apical sodium-dependent bile acid transporter inhibition with volixibat in healthy adults and patients with type 2 diabetes mellitus: a randomised placebo-controlled trial.BMC gastroenterology · 2018Trial
- Mutually exclusive alternative pre-mRNA splicing promotes adaptive metabolic stress signaling by JNK.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Functions of FGF21 and its role in cardiac hypertrophy.Journal of advanced research · 2026Review
- Article
- Gut-liver axis in diabetes: Mechanisms and therapeutic opportunities.World journal of gastroenterology · 2025Review
- Treating metabolic dysfunction-associated steatohepatitis: The fat-trimming FGF21 approach.Obesity reviews : an official journal of the International Association for the Study of Obesity · 2025Review
- Targeting the AMP-activated protein kinase pathway: the active metabolites of botanical drugs represent potential strategies for treating metabolic-associated fatty liver disease.Frontiers in pharmacology · 2025Review
- The interplay between nutrigenomics and low-carbohydrate ketogenic diets in personalized healthcare.Frontiers in nutrition · 2025Review
- Dietary high lipid and high plant-protein affected growth performance, liver health, bile acid metabolism and gut microbiota in groupers.Animal nutrition (Zhongguo xu mu shou yi xue hui) · 2024Article
- Potential therapeutic strategies for MASH: from preclinical to clinical development.Life metabolism · 2024Review
- FGF21-dependent alleviation of cholestasis-induced liver fibrosis by sodium butyrate.Frontiers in pharmacology · 2024Article
- Herb-drug interactions of silybinin and cilofexor in beagle dogs based on pharmacokinetics by UPLC-MS/MS.Frontiers in pharmacology · 2024Article
- MAPL loss dysregulates bile and liver metabolism in mice.EMBO reports · 2023Article
- Recent insights into the pathogenesis and therapeutic targets of chronic liver diseases.eGastroenterology · 2023Article
- Thioredoxin/Glutaredoxin Systems and Gut Microbiota in NAFLD: Interplay, Mechanism, and Therapeutical Potential.Antioxidants (Basel, Switzerland) · 2023Review
- Recent progress in understanding mitokines as diagnostic and therapeutic targets in hepatocellular carcinoma.World journal of clinical cases · 2023Review
- Targeting fibrosis, mechanisms and cilinical trials.Signal transduction and targeted therapy · 2022Review
22 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
Previous studies have shown that starvation or consumption of a high fat, low carbohydrate (HF-LC) ketogenic diet induces hepatic fibroblast growth factor 21 (FGF21) gene expression in part by activating the peroxisome proliferator-activated receptor-α (PPARα). Using primary hepatocyte cultures to screen for endogenous signals that mediate the nutritional regulation of FGF21 expression, we identified two sources of PPARα activators (i.e. nonesterified unsaturated fatty acids and chylomicron remnants) that induced FGF21 gene expression. In addition, we discovered that natural (i.e. bile acids) and synthetic (i.e. GW4064) activators of the farnesoid X receptor (FXR) increased FGF21 gene expression and secretion. The effects of bile acids were additive with the effects of nonesterified unsaturated fatty acids in regulating FGF21 expression. FXR activation of FGF21 gene transcription was mediated by an FXR/retinoid X receptor binding site in the 5'-flanking region of the FGF21 gene. FGF19, a gut hormone whose expression and secretion is induced by intestinal bile acids, also increased hepatic FGF21 secretion. Deletion of FXR in mice suppressed the ability of an HF-LC ketogenic diet to induce hepatic FGF21 gene expression. The results of this study identify FXR as a new signaling pathway activating FGF21 expression and provide evidence that FXR activators work in combination with PPARα activators to mediate the stimulatory effect of an HF-LC ketogenic diet on FGF21 expression. We propose that the enhanced enterohepatic flux of bile acids during HF-LC consumption leads to activation of hepatic FXR and FGF19 signaling activity and an increase in FGF21 gene expression and secretion.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.