Department of Medicine III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany.
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Aliment Pharmacol Ther. 2023 Jul;58(2):238-249. doi: 10.1111/apt.17566. Epub 2023 May 29.
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.
To examine the effects of missense variants in MTTP on hepatic and circulating lipids.
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).
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.
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.
微粒体甘油三酯转移蛋白（MTP；基因名称 MTTP）的遗传失活和药理抑制可抑制 VLDL 的肝分泌，从而降低血清脂质和载脂蛋白 B，但代价是增加肝脂肪变性。
研究 MTTP 错义变异对肝和循环脂质的影响。
我们分析了 MTTP 错义变异与宾夕法尼亚大学医学生物库（PMBB；n=37960）和英国生物库（UKB；n=451444）的代谢、肝和临床表型的关联。
我们在 PMBB 中分析了 MTTP 的 24 个错义变异与活检证实的肝脂肪变性的关联，发现异亮氨酸 128 到苏氨酸变异（I128T：rs3816873-A，频率 26%）与脂肪变性减少相关（p<0.001）。PMBB 影像学证实的脂肪变性患者的载脂蛋白也明显少于对照组。UKB 的分析也表明，MTTP I128T 与肝脂肪变性风险降低相关。出乎意料的是，MTTP I128T 与 LDL-胆固醇和载脂蛋白 B 血浆水平降低相关（均 p<0.001）。功能研究表明，MTTP I128T 既不是经典的失活也不是获得功能等位基因。
MTTP I128T 与肝脂肪变性减少以及血浆脂质和载脂蛋白 B 减少相关。这种矛盾的特征与 MTP 活性的简单获得或丧失功能不一致，表明对 MTP 功能有更复杂的影响。进一步研究 MTTP I128T 将为 MTP 结构-功能提供深入了解，并可能为调节 MTP 活性提供新方法，从而降低肝和循环脂质。
