Effects of TM6SF2 E167K on hepatic lipid and very low-density lipoprotein metabolism in humans

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Boren , J , Adiels , M , Bjornson , E , Matikainen , N , Söderlund , S , Rämö , J , Ståhlman , M , Ripatti , P , Ripatti , S , Palotie , A , Mancina , R M , Hakkarainen , A , Romeo , S , Packard , C J & Taskinen , M-R 2020 , ' Effects of TM6SF2 E167K on hepatic lipid and very low-density lipoprotein metabolism in humans ' , JCI INSIGHT , vol. 5 , no. 24 , 144079 . https://doi.org/10.1172/jci.insight.144079

Title: Effects of TM6SF2 E167K on hepatic lipid and very low-density lipoprotein metabolism in humans
Author: Boren, Jan; Adiels, Martin; Bjornson, Elias; Matikainen, Niina; Söderlund, Sanni; Rämö, Joel; Ståhlman, Marcus; Ripatti, Pietari; Ripatti, Samuli; Palotie, Aarno; Mancina, Rosellina M.; Hakkarainen, Antti; Romeo, Stefano; Packard, Chris J.; Taskinen, Marja-Riitta
Other contributor: University of Helsinki, HUS Abdominal Center
University of Helsinki, Clinicum
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Samuli Olli Ripatti / Principal Investigator
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Centre of Excellence in Complex Disease Genetics
University of Helsinki, HUS Medical Imaging Center
University of Helsinki, HUS Heart and Lung Center




















Date: 2020-12-17
Language: eng
Number of pages: 9
Belongs to series: JCI INSIGHT
ISSN: 2379-3708
DOI: https://doi.org/10.1172/jci.insight.144079
URI: http://hdl.handle.net/10138/325195
Abstract: Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation. The transmembrane 6 superfamily member 2 (TM6SF2) E167K genetic variant associates with NAFLD and with reduced plasma triglyceride levels in humans. However, the molecular mechanisms underlying these associations remain unclear. We hypothesized that TM65F2 E167K affects hepatic very low-density lipoprotein (VLDL) secretion and studied the kinetics of apolipoprotein 13100 (apoB100) and triglyceride metabolism in VLDL in homozygous subjects. In 10 homozygote TM6SF2 E167K carriers and 10 matched controls, we employed stable-isotope tracer and compartmental modeling techniques to determine apoB100 and triglyceride kinetics in the 2 major VIOL subtractions: large triglyceride-rich VLDL, and smaller, less triglyceride-rich VLDL2. VLDL1-apoB100 production was markedly reduced in homozygote TM6SF2 E167K carriers compared with controls. Likewise. VLDL,-triglyceride production was 35% lower in the TMSSF2 E167K carriers. In contrast, the direct production rates for VLDL2 apo13100 and triglyceride were not different between carriers and controls. In conclusion, the TM6SF2 E167K genetic variant was linked to a specific reduction in hepatic secretion of large triglyceride-rich VLDL1. The impaired secretion of VLDL1 explains the reduced plasma triglyceride concentration and provides a basis for understanding the lower risk of cardiovascular disease associated with the TM6SF2 E167K genetic variant.
Subject: FATTY LIVER-DISEASE
DE-NOVO LIPOGENESIS
INSULIN-RESISTANCE
CONFERS SUSCEPTIBILITY
VARIANT
VLDL
SECRETION
ACIDS
OVERPRODUCTION
CHOLESTEROL
3111 Biomedicine
3121 General medicine, internal medicine and other clinical medicine
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