Polymorphism in microsomal triglyceride transfer protein: a link between liver disease and atherogenic postprandial lipid profile in NASH?
Nonalcoholic fatty liver disease (NAFLD) is emerging as an independent cardiovascular risk factor, but mechanism(s) linking fatty liver to atherosclerosis are unknown. Microsomal triglyceride transfer protein (MTP) -493 G/T polymorphism modulates circulating lipid and lipoprotein levels in different subsets and has been linked to NAFLD. The impact of MTP -493 G/T polymorphism, adipokines, and diet on postprandial lipoprotein profile and liver disease was assessed in nonalcoholic steatohepatitis (NASH). Plasma lipids, triglyceride-rich lipoprotein subfractions, high-density lipoprotein-C (HDL-C), and oxidized low-density lipoprotein (LDL) after an oral fat load were cross-sectionally correlated to MTP -493 G/T polymorphism, dietary habits, adipokines, and liver histology in 29 nonobese nondiabetic patients with NASH and 27 healthy controls. The severity of liver histology, the magnitude of triglycerides (Tg), free fatty acid (FFA), and LDL-conjugated diene responses, and the fall in HDL-C and apoA1 were significantly higher in NASH G/G (66% of patients) than in the other genotypes, despite similar adipokine profile and degree of insulin resistance. Postprandial large intestinal very-low-density lipoprotein (VLDL) subfraction A increases independently predicted Tg (beta=0.48; P=.008), FFA (beta=0.47; P=0.010), HDL-C (beta=0.42; P=0.009), and LDL-conjugated diene (beta=0.52; P=0.002) responses. VLDL A apoB48 response was independently associated with liver steatosis (OR: 2.4; CI 1.7-9.6; P=0.031). Postprandial LDL-conjugated diene response predicted severe necroinflammation (OR: 3.3; CI 1.4-9.7; P=0.016) and fibrosis (OR: 2.8; CI 1.0-8,5; P=0.030); postprandial apoA1 fall predicts severe fibrosis (OR: 2.1; CI: 1.5-6.1; P=0.015).


CONCLUSIONS
MTP -493 G/T polymorphism may impact NASH by modulating postprandial lipemia and lipoprotein metabolism; homozygous GG carriers have a more atherogenic postprandial lipid profile than the other genotypes, independently of adipokines and insulin resistance.
Gambino
Roberto
R
Department of Internal Medicine, University of Turin, and Gradenigo Hospital, Italy.
Cassader
Maurizio
M
Pagano
Gianfranco
G
Durazzo
Marilena
M
Musso
Giovanni
G
D000328:Adult; D001055:Apolipoproteins B / Q000097:blood / Q000235:genetics; D050197:Atherosclerosis / Q000097:blood* / Q000209:etiology*; D002352:Carrier Proteins / Q000235:genetics*; D003430:Cross-Sectional Studies; D005234:Fatty Liver / Q000150:complications / Q000235:genetics*; D005260:Female; D006801:Humans; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood*; D008079:Lipoproteins, VLDL / Q000097:blood; D008297:Male; D011110:Polymorphism, Genetic; D019518:Postprandial Period
D001055:Apolipoproteins B; D002352:Carrier Proteins; D008055:Lipids; D008079:Lipoproteins, VLDL; C106092:microsomal triglyceride transfer protein