MERTK rs4374383 variant predicts incident nonalcoholic fatty liver disease and diabetes: role of mononuclear cell activation and adipokine response to dietary fat

• Published in: Human molecular genetics 2017-05, Vol.26 (9), p.1747-1758
• Main Authors: Musso, Giovanni, Cassader, Maurizio, De Michieli, Franco, Paschetta, Elena, Pinach, Silvia, Saba, Francesca, Bongiovanni, Daria, Framarin, Luciana, Berrutti, Mara, Leone, Nicola, Corvisieri, Stefania, Parente, Renato, Molinaro, Federica, Sircana, Antonio, Bo, Simona, Gambino, Roberto
• Format: Article
• Language: English
• Subjects: Adipokines - metabolism; c-Mer Tyrosine Kinase; Cohort Studies; Cross-Sectional Studies; Diabetes Mellitus - genetics; Diabetes Mellitus - metabolism; Dietary Fats - metabolism; Female; Genetic Predisposition to Disease; Genetic Variation; Glucose - metabolism; Humans; Insulin Resistance - genetics; Leukocytes, Mononuclear - metabolism; Lipid Metabolism; Lipoproteins - genetics; Liver Cirrhosis - metabolism; Male; Middle Aged; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - metabolism; Polymorphism, Single Nucleotide; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - metabolism
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddw400

The loss-of-function rs4374383 G > A variant in Myeloid-epithelial-reproductive Tyrosine Kinase (MERTK) gene has been linked to hepatic fibrosis in chronic liver diseases. MERTK is expressed by immune and non-immune cells involved in inflammation, metabolism and vascular homeostasis. We assessed the impact of MERTK rs4374383 G > A variant on nonalcoholic fatty liver disease (NAFLD) incidence and severity and on glucose and lipid metabolism. We followed-up 305 healthy nonobese nondiabetic, metabolic syndrome-free insulin sensitive participants in a population-based study, characterized for MERTK G > A polymorphism, adipokine profile and inflammatory markers.An independent cohort of 69 biopsy-proven nondiabetic NAFLD patients and 69 healthy controls underwent indirect calorimetry, an OGTT with Minimal Model analysis of glucose homeostasis, and an oral fat tolerance test with measurement of plasma lipoproteins, adipokines, MCP-1, and of Nuclear Factor (NF)-κB activation in circulating mononuclear cells (MNCs). In the longitudinal cohort, MERTK G > A polymorphism protected against 9-year incident NAFLD (OR:0.48,95%CI:0.26-0.79) and diabetes (OR: 0.47, 95% CI: 0.19-0.87).In the cross-sectional cohort, MERTK A-allele carriers had higher fat oxidation rates and tissue insulin sensitivity. Despite comparable fastign and postprandial lipid profiles, MERTK A-allele carriers showed lower resistin and MCP-1 responses, milder MNC NF-κB activation, and a higher postprandial adiponectin response to fat, which predicted tissue insulin resistance hepatocyte apoptosis and liver histology. MERTK G > A variant affects liver disease, nutrient oxidation and glucose metabolism in NAFLD. The modulation of adipokine, chemokine and pro-inflammatory MNC activation in response to fat ingestion may contribute to the observed effects on liver and metabolic disease.