The Cholesterol Derivative 27-Hydroxycholesterol Reduces Steatohepatitis in Mice
| Autor: | Patrick J. van Gorp, Veerle Bieghs, Mike L. J. Jeurissen, Satish C. Kalhan, Ronit Sverdlov, Yasmin Dias Guichot, Sander S. Rensen, Jogchum Plat, Marion J.J. Gijbels, Aalt Bast, Eran Leitersdorf, Dieter Lütjohann, Marten H. Hofker, Ger H. Koek, Tim Hendrikx, Fons Verheyen, Sofie M. A. Walenbergh |
|---|---|
| Přispěvatelé: | Moleculaire Genetica, Pathologie, Genetica & Celbiologie, Surgery, Farmacologie en Toxicologie, Humane Biologie, RS: NUTRIM - R3 - Chronic inflammatory disease and wasting, RS: NUTRIM - R2 - Gut-liver homeostasis, RS: NUTRIM - R1 - Metabolic Syndrome, Metamedica, Interne Geneeskunde, RS: CARIM School for Cardiovascular Diseases, RS: GROW - School for Oncology and Reproduction, Medical Biochemistry, Center for Liver, Digestive and Metabolic Diseases (CLDM), Vascular Ageing Programme (VAP) |
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Male
HOMEOSTASIS Gene Expression Hepatitis Cholesterol Dietary chemistry.chemical_compound Mice Non-alcoholic Fatty Liver Disease CYP27A1 ATP Binding Cassette Transporter Subfamily G Member 1 Bone Marrow Transplantation Liver X Receptors Mice Knockout Metabolic Syndrome OXYSTEROLS NONALCOHOLIC STEATOHEPATITIS Fatty liver Gastroenterology Alanine Transaminase Orphan Nuclear Receptors Lipids Liver 27-Hydroxycholesterol Cholestanetriol 26-Monooxygenase lipids (amino acids peptides and proteins) Female medicine.symptom Sterol Regulatory Element Binding Protein 1 ATP Binding Cassette Transporter 1 medicine.medical_specialty Kupffer Cells Lipoproteins LOW-DENSITY-LIPOPROTEIN Antigens Differentiation Myelomonocytic Inflammation STEROL 27-HYDROXYLASE GENE Biology METABOLISM INFLAMMATION Antigens CD Internal medicine NAFLD medicine Animals Humans Liver X receptor Triglycerides FATTY LIVER-DISEASE Mouse Model Hepatology Cholesterol medicine.disease Dietary Fats Hydroxycholesterols Fatty Liver Endocrinology chemistry Receptors LDL ATHEROSCLEROSIS ATP-Binding Cassette Transporters Steatosis Steatohepatitis Lysosomes Foam Cells BILE-ACID |
| Zdroj: | Gastroenterology, 144(1), 167-178.e1. Elsevier Saunders Gastroenterology, 144(1), 167-178. W.B. Saunders Ltd Gastroenterology, 144(1), 167-U291. W B SAUNDERS CO-ELSEVIER INC |
| ISSN: | 0016-5085 |
| DOI: | 10.1053/j.gastro.2012.09.062 |
| Popis: | Background & Aims Non-alcoholic steatohepatitis is characterized by hepatic steatosis with inflammation. Although steatosis is benign and reversible, inflammation can increase liver damage. Hepatic inflammation has been associated with accumulation of cholesterol in lysosomes of Kupffer cells. 27-Hydroxycholesterol (27HC), a derivative of cholesterol formed by CYP27A1, can mobilize cholesterol from the lysosomes to the cytoplasm. We investigated whether 27HC can change the intracellular distribution cholesterol and reduce hepatic inflammation in mice. Methods We transplanted bone marrow from irradiated wild-type or Cyp27a1 −/− mice to mice that do not express the low density lipoprotein receptor ( Ldlr −/− ), which are hyperlipidemic; 9 weeks later, mice were fed either regular chow or a high-fat, high-cholesterol (HFC) diet for 3 months. In a separate experiment, Ldlr −/− mice were given subcutaneous injections of 27HC and placed on regular chow or HFC diets for 3 weeks. Blood and liver tissues samples were collected and analyzed for intracellular cholesterol distribution and inflammation. Results In Ldlr −/− mice that received bone marrow transplants from Cyp27a1 −/− mice, lysosomes of Kupfer cells had a greater accumulation of cholesterol than those of mice that received bone marrow from wild-type mice, after the HFC diet. Liver histology and gene expression analyses showed increased inflammation and liver damage in mice given bone marrow transplants from Cyp27a1 −/− mice and placed on the HFC diet. Administration of 27HC to Ldlr −/− mice, following the HFC diet, reduced the accumulation of lysosomal cholesterol and hepatic inflammation, compared with mice that were not given 27HC. Conclusions Accumulation of cholesterol in lysosomes of Kupfer cells promotes hepatic inflammation in mice. The cholesterol derivative 27HC reduces accumulation of cholesterol in lysosomes and might be used to treat non-alcoholic steatohepatitis. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|