1. Effects of TM6SF2 E167K on hepatic lipid and very low-density lipoprotein metabolism in humans
- Author
-
Elias Björnson, Sanni Söderlund, Pietari Ripatti, Antti Hakkarainen, Marcus Ståhlman, Aarno Palotie, Niina Matikainen, Joel T. Rämö, Rosellina Margherita Mancina, Chris J. Packard, Jan Borén, Stefano Romeo, Samuli Ripatti, Martin Adiels, Marja-Riitta Taskinen, HUS Abdominal Center, Clinicum, CAMM - Research Program for Clinical and Molecular Metabolism, Research Programs Unit, Faculty of Medicine, Endokrinologian yksikkö, University of Helsinki, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, Complex Disease Genetics, Helsinki Institute of Life Science HiLIFE, Samuli Olli Ripatti / Principal Investigator, Doctoral Programme in Social Sciences, Centre of Excellence in Complex Disease Genetics, Department of Public Health, University Management, Biostatistics Helsinki, Aarno Palotie / Principal Investigator, HUS Medical Imaging Center, Department of Diagnostics and Therapeutics, and HUS Heart and Lung Center
- Subjects
Male ,0301 basic medicine ,Very low-density lipoprotein ,Apolipoprotein B ,VARIANT ,lcsh:Medicine ,Lipoproteins, VLDL ,chemistry.chemical_compound ,0302 clinical medicine ,Non-alcoholic Fatty Liver Disease ,Nonalcoholic fatty liver disease ,CONFERS SUSCEPTIBILITY ,INSULIN-RESISTANCE ,biology ,Chemistry ,CHOLESTEROL ,General Medicine ,Middle Aged ,Lipids ,3. Good health ,Lipoproteins, LDL ,Liver ,030220 oncology & carcinogenesis ,Apolipoprotein B-100 ,Lipogenesis ,Medicine ,SECRETION ,Female ,VLDL ,Research Article ,medicine.medical_specialty ,Lipoproteins ,OVERPRODUCTION ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,Internal medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,Triglycerides ,DE-NOVO LIPOGENESIS ,FATTY LIVER-DISEASE ,Triglyceride ,Hepatology ,Cholesterol ,lcsh:R ,Membrane Proteins ,Lipase ,Lipid Metabolism ,medicine.disease ,ACIDS ,Metabolism ,030104 developmental biology ,Endocrinology ,3121 General medicine, internal medicine and other clinical medicine ,biology.protein ,3111 Biomedicine ,TM6SF2 ,Lipoprotein - 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.
- Published
- 2020