A coding variant in the microsomal triglyceride transfer protein reduces both hepatic steatosis and plasma lipids

Abstract

Summary Background Genetic inactivation and pharmacologic inhibition of the microsomal triglyceride transfer protein (MTP; gene name MTTP) inhibits hepatic secretion of VLDL, thereby reducing serum lipids and apoB at the expense of increasing hepatic steatosis. Aim To examine the effects of missense variants in MTTP on hepatic and circulating lipids. Methods We analysed the association of MTTP missense variants with metabolic, hepatic and clinical phenotypes in the Penn Medicine Biobank (PMBB; n = 37,960) and the UKBiobank (UKB; n = 451,444). Results We analysed 24 missense variants in MTTP in PMBB for association with biopsy‐proven hepatic steatosis and found that an isoleucine 128 to threonine variant (I128T: rs3816873‐A, frequency 26%) was associated with reduced steatosis (p < 0.001). PMBB subjects with imaging‐proven steatosis also revealed significantly fewer carriers of MTTP I128T compared to controls. Analysis in UKB also showed that MTTP I128T was associated with reduced risk of hepatic steatosis. Unexpectedly, MTTP I128T was found to be associated with reduced plasma levels of LDL‐cholesterol and apoB (all p < 0.001). Functional studies indicated that MTTP I128T is neither a classic loss nor gain of function allele. Conclusions MTTP I128T is associated with reduced hepatic steatosis as well as reduced plasma lipids and apoB. This paradoxical profile is not consistent with a simple gain or loss of function in MTP activity and suggests a more complex effect on MTP function. Further investigation of MTTP I128T will provide insight into the structure–function of MTP and potentially new approaches to modulate MTP activity that could both reduce hepatic and circulating lipids.

Association between MTTP genotype (-493G/T) polymorphism and hepatic steatosis in hepatitis C: a systematic review and meta-analysis

“…HCV viral particles contain apolipoproteins, whereby their production and secretion depend on very low-density lipoprotein (VLDL) and other types of apolipoproteins [ 29 , 30 ]. MTTP is involved in the assembly and secretion of VLDL and ApoB [ 31 ]. Consequently, enhanced transcriptional activity of MTTP produces higher levels of VLDL, increasing the ability to assemble, produce and replicate HCV virus particles [ 32 , 33 ].…”

Editorial: MTTP, hepatic steatosis and plasma lipids – still more questions than answers

“…Schneider et al 6 evaluated associations between NAFLD, lipid levels and variants in MTTP , which encodes the microsomal triglyceride transfer protein (MTP) that promotes secretion of very low density lipoproteins (VLDL) from the liver into the circulation. They first found in Penn Medicine Biobank (PMBB) that MTTP ‐rs3816873‐A (I128T) lowered the risk of biopsy‐confirmed hepatic steatosis.…”

Editorial: MTTP, hepatic steatosis, and plasma lipids—still more questions than answers. Authors' reply

“…We appreciate the editorial response to our recently published article 1,2 . It aptly encapsulated the core findings and implications of our research for nonalcoholic fatty liver disease (NAFLD), its genetic underpinnings, 3 and the related cardiovascular disease (CVD) risks 1,4–6 .…”