MERTK rs4374383 variant predicts incident nonalcoholic fatty liver disease and diabetes: role of mononuclear cell activation and adipokine response to dietary fat.
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.
HUMANITAS Gradenigo, Turin, Italy.
Giovanni
G
Musso
Department of Medical Sciences, University of Turin, Italy.
Maurizio
M
Cassader
Department of Medical Sciences, University of Turin, Italy.
Franco
F
De Michieli
HUMANITAS Gradenigo, Turin, Italy.
Elena
E
Paschetta
Department of Medical Sciences, University of Turin, Italy.
Silvia
S
Pinach
Department of Medical Sciences, University of Turin, Italy.
Francesca
F
Saba
HUMANITAS Gradenigo, Turin, Italy.
Daria
D
Bongiovanni
HUMANITAS Gradenigo, Turin, Italy.
Luciana
L
Framarin
HUMANITAS Gradenigo, Turin, Italy.
Mara
M
Berrutti
HUMANITAS Gradenigo, Turin, Italy.
Nicola
N
Leone
University of Turin, Italy.
Stefania
S
Corvisieri
HUMANITAS Gradenigo, Turin, Italy.
Renato
R
Parente
HUMANITAS Gradenigo, Turin, Italy.
Federica
F
Molinaro
Antonio
A
Sircana
Department of Medical Sciences, University of Turin, Italy.
Simona
S
Bo
Department of Medical Sciences, University of Turin, Italy.
Roberto
R
Gambino
D054392:Adipokines / Q000378:metabolism; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D003920:Diabetes Mellitus / Q000235:genetics* / Q000378:metabolism; D004041:Dietary Fats / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000235:genetics; D008103:Liver Cirrhosis / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism*; D000076202:c-Mer Tyrosine Kinase
D054392:Adipokines; D004041:Dietary Fats; D008074:Lipoproteins; D011518:Proto-Oncogene Proteins; C097072:MERTK protein, human; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase; D005947:Glucose