Impaired Generation of 12-Hydroxylated Bile Acids Links Hepatic Insulin Signaling with Dyslipidemia
| Autor: | Carrie L. Welch, Matthew Pratt-Hyatt, Curtis D. Klaassen, Rebecca A. Haeusler, Domenico Accili |
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| Rok vydání: | 2012 |
| Předmět: |
Male
medicine.medical_specialty Very low-density lipoprotein medicine.drug_class Physiology medicine.medical_treatment Receptors Cytoplasmic and Nuclear 030209 endocrinology & metabolism Type 2 diabetes Biology Hydroxylation Article Bile Acids and Salts 03 medical and health sciences Mice 0302 clinical medicine Internal medicine medicine Animals Insulin Steroid 12-alpha-Hydroxylase Molecular Biology Triglycerides 030304 developmental biology Dyslipidemias Mice Knockout 0303 health sciences Bile acid Forkhead Box Protein O1 Lipid metabolism Forkhead Transcription Factors Isoxazoles Cell Biology medicine.disease Lipid Metabolism 3. Good health Insulin receptor Endocrinology Glucose Diabetes Mellitus Type 2 Liver biology.protein Metabolome lipids (amino acids peptides and proteins) Metabolic syndrome CYP8B1 Signal Transduction |
| Zdroj: | Cell Metabolism. 15(1):65-74 |
| ISSN: | 1550-4131 |
| DOI: | 10.1016/j.cmet.2011.11.010 |
| Popis: | SummaryThe association of type 2 diabetes with elevated plasma triglyceride (TG) and very low-density lipoproteins (VLDL), and intrahepatic lipid accumulation represents a pathophysiological enigma and an unmet therapeutic challenge. Here, we uncover a link between insulin action through FoxO1, bile acid (BA) composition, and altered lipid homeostasis that brings new insight to this longstanding conundrum. FoxO1 ablation brings about two signature lipid abnormalities of diabetes and the metabolic syndrome, elevated liver and plasma TG. These changes are associated with deficiency of 12α-hydroxylated BAs and their synthetic enzyme, Cyp8b1, that hinders the TG-lowering effects of the BA receptor, Fxr. Accordingly, pharmacological activation of Fxr with GW4064 overcomes the BA imbalance, restoring hepatic and plasma TG levels of FoxO1-deficient mice to normal levels. We propose that generation of 12α-hydroxylated products of BA metabolism represents a signaling mechanism linking hepatic lipid abnormalities with type 2 diabetes, and a treatment target for this condition. |
| Databáze: | OpenAIRE |
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