PAR2 controls cholesterol homeostasis and lipid metabolism in nonalcoholic fatty liver disease
| Autor: | Elizabeth K. Fletcher, Athan Kuliopulos, Nga Nguyen, Srijoy Guha, Andrew Shearer, Daniel H. Cox, James D. Baleja, Ying Wang, Manal F. Abdelmalek, Lidija Covic, Rajashree Rana |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Liver Cirrhosis
Male 0301 basic medicine GTP-Binding Protein alpha Subunits Gi-Go Mice chemistry.chemical_compound 0302 clinical medicine Non-alcoholic Fatty Liver Disease Nonalcoholic fatty liver disease Mice Knockout NAS NAFLD activity score medicine.diagnostic_test Bile acid Reverse cholesterol transport Fatty liver NASH Middle Aged 3. Good health medicine.anatomical_structure Cholesterol Liver Fib Fibrosis Liver biopsy Hepatocyte JNK c-Jun N-terminal kinase Disease Progression Female Original Article NASH nonalcoholic steatohepatitis Adult medicine.medical_specialty lcsh:Internal medicine medicine.drug_class 030209 endocrinology & metabolism Diet High-Fat 03 medical and health sciences PAR2 Protease-Activated Receptor 2 Protease-activated receptor 2 Internal medicine medicine Animals Humans Mitogen-Activated Protein Kinase 9 Receptor PAR-2 Mitogen-Activated Protein Kinase 8 lcsh:RC31-1245 Molecular Biology Aged business.industry Lipid metabolism Cell Biology Energy metabolism Lipid Metabolism medicine.disease Mice Inbred C57BL 030104 developmental biology Endocrinology chemistry Lipid Peroxidation NAFLD nonalcoholic fatty liver disease business |
| Zdroj: | Molecular Metabolism, Vol 29, Iss, Pp 99-113 (2019) Molecular Metabolism |
| ISSN: | 2212-8778 |
| Popis: | Objective Increases in hepatic and plasma cholesterol occur in patients with nonalcoholic fatty liver disease (NAFLD), although the reason for this is not well understood. We investigated whether Protease-Activated Receptor 2 (PAR2) plays a role in cholesterol and lipid homeostasis in NAFLD. Methods Human liver biopsies (n = 108) were quantified for PAR2 expression from NAFLD cases randomly selected and stratified by liver fibrosis stage, the primary predictor for clinical outcomes, while controlling for age, gender, and BMI between fibrosis groups. Demographic data and laboratory studies on plasma samples were obtained within 6 months of liver biopsy. Wild-type and PAR2-KO (C57BL/6 F2rl1−/−) mice were fed either normal or high fat diet for 16 weeks and plasma and liver assayed for lipids and soluble metabolites. Results Severity of NAFLD and plasma cholesterol levels significantly correlated with hepatocyte PAR2 expression in NAFLD patients. Conversely, PAR2 deficiency in mice resulted in reduced expression of key hepatic genes involved in cholesterol synthesis, a 50% drop in plasma and total liver cholesterol, and induced a reverse cholesterol transport system that culminated in 25% higher fecal bile acid output. PAR2-deficient mice exhibited enhanced fatty acid β-oxidation with a ketogenic shift and an unexpected increase in liver glycogenesis. Mechanistic studies identified Gi-Jnk1/2 as key downstream effectors of protease-activated PAR2 in the regulation of lipid and cholesterol homeostasis in liver. Conclusions These data indicate that PAR2 may be a new target for the suppression of plasma cholesterol and hepatic fat accumulation in NAFLD and related metabolic conditions. Highlights • Increases in cholesterol in NAFLD and NASH is a vexing problem. • PAR2 has been identified as a connecting hub between metabolism and fibrosis. • Severity of NAFLD and cholesterol correlate with hepatocyte PAR2 expression. • PAR2 suppresses reverse cholesterol transport and lipid breakdown in liver. |
| Databáze: | OpenAIRE |
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