MTTP-297H polymorphism reduced serum cholesterol but increased risk of non-alcoholic fatty liver disease-a cross-sectional study

Abstract

Background: Microsomal triglyceride transfer protein (MTP) works to lipidate and assemble the apoB-containing lipoproteins in liver. It closely links up the hepatic secretion of lipid to regulate serum lipid and atherosclerosis. Cases of MTTP gene mutation is characterized by abetalipoproteinemia and remarkable hepatic steatosis or cirrhosis. Several MTTP polymorphisms have been reported relating to metabolic syndrome, hyperlipidemia and steatohepatitis. We supposed the regulation of serum lipids and risk of non-alcoholic fatty liver disease (NAFLD) formation may be modified by individual susceptibility related to the MTTP polymorphisms. Methods and results: A cross-sectional population of 1193 subjects, 1087 males and 106 females mean aged 45.9 ± 8.9 years, were enrolled without recognized secondary hyperlipidemia. Fasting serum lipid, insulin, and non-esterified fatty acid were assessed and transformed to insulin resistance index, HOMA-IR and Adipo-IR. After ruling out alcohol abuser, non-alcoholic fatty liver disease (NAFLD) was diagnosed by abdominal ultrasound. Five common MTTP polymorphisms (promoter -493G/T, E98D, I128T, N166S, and Q297H) were conducted by TaqMan assay. Multivariate regression analysis was used to estimate their impact on serum lipid and NAFLD risk. Assessment revealed a differential impact on LDL-C and non-HDL-C, which were sequentially determined by the Q297H polymorphism, insulin resistance, body mass index and age. Carriers of homozygous minor allele (297H) had significantly lower LDL-C and non-HDL-C but higher risk for NAFLD. Molecular modeling of the 297H variant demonstrated higher free energy, potentially referring to an unstable structure and functional sequence. Conclusion: These results evidenced the MTTP polymorphisms could modulate the lipid homeostasis to determine the serum lipids and risk of NAFLD. The MTTP 297H polymorphism interacted with age, insulin resistance and BMI to decrease serum apoB containing lipoproteins (LDL-C and non-HDL-C) but increase the risk of NAFLD formation.