ArticleGenes & development2009
Bile acid signaling pathways increase stability of Small Heterodimer Partner (SHP) by inhibiting ubiquitin-proteasomal degradation.
Article in Genes & development, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 85 papers.
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Who cites it
85 citing papers in PubMed, 126 citations in OpenAlex.
- The role of FGF19-FGFR4 signaling pathway in liver health and disease: Guardian or destroyer.Genes & diseases · 2026Review
- Cafestol-derivatives as potential FXR agonists and CYP7A1 inhibitors and their impact on hypercholesterolemia: an in silico study.Scientific reports · 2026Article
- Enhanced nuclear localization of small heterodimer partner in metabolic dysfunction-associated steatohepatitis.JHEP reports : innovation in hepatology · 2026Article
- Hepatic protein kinase Cβ antagonizing p38American journal of physiology. Gastrointestinal and liver physiology · 2025Article
- The mood stabilizers lithium and valproate disrupt hepatic and intestinal farnesoid X receptor signalling and increase bile synthesis in the rat.Experimental physiology · 2025Article
- Orphan Nuclear Receptors in Metabolic Dysfunction-associated Steatotic Liver Disease Development.Journal of clinical and translational hepatology · 2025Review
- Intermittent fasting and metabolic dysfunction-associated steatotic liver disease: the potential role of the gut-liver axis.Cell & bioscience · 2025Review
- Bile Acid Signaling in Metabolic and Inflammatory Diseases and Drug Development.Pharmacological reviews · 2024Review
- Direct Molecular Action of Taurine on Hepatic Gene Expression Associated with the Amelioration of Hypercholesterolemia in Rats.Antioxidants (Basel, Switzerland) · 2024Article
- Bile acid metabolism and signaling in health and disease: molecular mechanisms and therapeutic targets.Signal transduction and targeted therapy · 2024Review
- FGF19 promotes nasopharyngeal carcinoma progression by inducing angiogenesis via inhibiting TRIM21-mediated ANXA2 ubiquitination.Cellular oncology (Dordrecht, Netherlands) · 2024Article
- The Crosstalk between Gut Microbiota and Bile Acids Promotes the Development of Non-Alcoholic Fatty Liver Disease.Microorganisms · 2023Review
- Bile Acids and Biliary Fibrosis.Cells · 2023Review
- Feeding activates FGF15-SHP-TFEB-mediated lipophagy in the gut.The EMBO journal · 2022Article
- Review
- Role of bile acids and their receptors in gastrointestinal and hepatic pathophysiology.Nature reviews. Gastroenterology & hepatology · 2022Review
- Fibroblast growth factor 15/19 expression, regulation, and function: An overview.Molecular and cellular endocrinology · 2022Review
- The role of bile acids in carcinogenesis.Cellular and molecular life sciences : CMLS · 2022Review
- Sleeve gastrectomy improves lipid dysmetabolism by downregulating the USP20-HSPA2 axis in diet-induced obese mice.Frontiers in endocrinology · 2022Article
- Article
25 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 4 institutions in 1 country.
Funding
Abstract
Small Heterodimer Partner (SHP) inhibits activities of numerous transcription factors involved in diverse biological pathways. As an important metabolic regulator, SHP plays a key role in maintaining cholesterol and bile acid homeostasis by inhibiting cholesterol conversion to bile acids. While SHP gene induction by increased bile acids is well established, whether SHP activity is also modulated remains unknown. Here, we report surprising findings that SHP is a rapidly degraded protein via the ubiquitin-proteasomal pathway and that bile acids or bile acid-induced intestinal fibroblast growth factor 19 (FGF19) increases stability of hepatic SHP by inhibiting proteasomal degradation in an extracellular signal-regulated kinase (ERK)-dependent manner. SHP was ubiquitinated at Lys122 and Lys123, and mutation of these sites altered its stability and repression activity. Tandem mass spectrometry revealed that upon bile acid treatment, SHP was phosphorylated at Ser26, within an ERK motif in SHP, and mutation of this site dramatically abolished SHP stability. Surprisingly, SHP stability was abnormally elevated in ob/ob mice and diet-induced obese mice. These results demonstrate an important role for regulation of SHP stability in bile acid signaling in normal conditions, and that abnormal stabilization of SHP may be associated with metabolic disorders, including obesity and diabetes.
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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.