Background And Aims: Cholestatic liver diseases (CLD) are often accompanied by hepatocellular injury, fibrosis, and cirrhosis due to the intracellular accumulation of solutes that cannot be excreted into bile, including bile acids (BAs). These are synthesized in hepatocytes from cholesterol mainly via the classic pathway and in a lower proportion through the mitochondrial acidic pathway. The latter requires STARD1-dependent cholesterol transport to the mitochondrial inner membrane for metabolism, whose contribution to BA-induced hepatotoxicity and CLD is unknown.
Approach And Results: Here we show that patients with primary biliary cholangitis exhibit increased expression of STARD1 compared to control subjects. Mice with hepatocyte-specific Stard1 deletion (Stard1Δhep) were more resistant to experimental models of complete (bile duct ligation, BDL) and chemical obstructive cholestasis-induced liver injury, inflammation and fibrosis than Stard1f/f mice. Stard1Δhep mice exhibited reduced hepatic BAs and mitochondrial cholesterol accumulation but increased mitochondrial GSH (mGSH) levels following BDL compared to Stard1f/f mice. Pharmacological mGSH depletion sensitized primary mouse hepatocytes to a mix of BAs mimicking the profile seen in Stard1f/f mice after BDL leading to increased inflammatory response and cytotoxicity.
Conclusions: These findings highlight a role for STARD1 in cholestatic liver injury and suggest that its targeting may be of relevance for CLD.
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http://dx.doi.org/10.1097/HEP.0000000000001184 | DOI Listing |
Hepatology
November 2024
Department of Medicine, Division of Gastroenterology and Hepatology, University of California Davis School of Medicine, Sacramento, California, USA.
Pediatr Surg Int
December 2024
Department of Pediatric Surgery, Medical and Dental Sciences Area, Research and Education Assembly, Research Field in Medicine and Health Sciences, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima City, 8900075, Japan.
Purpose: Cholestatic liver damage is frequently observed in extremely low-birth-weight infants (ELBWIs) followed by enterostomy. We retrospectively investigated the factors related to liver damage.
Methods: ELBWIs who underwent enterostomy at our institution between January 2013 and December 2022 for gastrointestinal disease during the neonatal period were reviewed.
Hepatol Commun
January 2025
Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, USA.
Cureus
November 2024
Department of Gastroenterology, Topiwala National Medical College & BYL Nair Charitable Hospital, Mumbai, IND.
A 12-year-old female, resident of western India, presented with a history of pruritus associated with jaundice for two months. On presentation, she had icterus with mild palpable hepatomegaly. Investigations revealed direct hyperbilirubinemia and elevated transaminases, while gamma-glutamyl transferase levels were normal.
View Article and Find Full Text PDFDiabetologia
December 2024
Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia.
Aims/hypothesis: Quinine, when administered intraduodenally to activate bitter-taste receptors, in a dose of 600 mg, stimulates glucagon-like peptide-1 (GLP-1) and insulin, slows gastric emptying and lowers postprandial glucose in healthy people, with consequent implications for the management of type 2 diabetes; the effect of quinine on energy intake is uncertain. We have investigated the dose-related effects of quinine on postprandial blood glucose levels and energy intake in people with type 2 diabetes.
Methods: Male participants with type 2 diabetes (age: 68±5 years; HbA: 49.
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