Impaired hepatic lipid synthesis from polyunsaturated fatty acids in TM6SF2 E167K variant carriers with NAFLD

Autor: Panu K. Luukkonen, Jeremy M. Palmer, Taru Tukiainen, Marja Leivonen, Marju Orho-Melander, Hannele Yki-Järvinen, Adnan Ali, Johanna Arola, Petter Vikman, Leif Groop, Matej Orešič, Tuulia Hyötyläinen, Emma Scott, P.A. Nidhina Haridas, Vesa M. Olkkonen, Quentin M. Anstee, You Zhou, Anne Juuti, Linda Ahonen, Om Prakash Dwivedi
Přispěvatelé: Department of Medicine, Clinicum, Institute for Molecular Medicine Finland, II kirurgian klinikka, Department of Surgery, Medicum, Department of Pathology, Leif Groop Research Group, Hannele Yki-Järvinen Research Group, HUS Internal Medicine and Rehabilitation, HUS Abdominal Center
Rok vydání: 2017
Předmět:
Male
0301 basic medicine
Apolipoprotein B
Lipoproteins
VLDL
chemistry.chemical_compound
ta318
chemistry.chemical_classification
INSULIN-RESISTANCE
biology
NONALCOHOLIC STEATOHEPATITIS
Middle Aged
Lipids
Transmembrane protein
3. Good health
Liver
Arachidonic acid
LOW-DENSITY LIPOPROTEINS
CARDIOVASCULAR-DISEASE
Phosphatidylethanolamine N-methyltransferase
Lipogenesis
Fatty Acids
Unsaturated
Phosphatidylcholines
Female
lipids (amino acids
peptides
and proteins)
Polyunsaturated fatty acid
Adult
Heterozygote
medicine.medical_specialty
Genotype
APOLIPOPROTEIN-B
Cholesterol esters
digestive system
03 medical and health sciences
Insulin resistance
LIVER-DISEASE
Internal medicine
medicine
Humans
Fatty acids
Triglycerides
Hepatology
PHOSPHATIDYLETHANOLAMINE N-METHYLTRANSFERASE
Membrane Proteins
nutritional and metabolic diseases
ARACHIDONIC-ACID
medicine.disease
digestive system diseases
030104 developmental biology
Endocrinology
chemistry
3121 General medicine
internal medicine and other clinical medicine
Hepatocytes
FIBROSIS PROGRESSION
biology.protein
Transmembrane 6 superfamily member 2
SUPERFAMILY MEMBER 2
Non-alcoholic fatty liver disease
TM6SF2
Zdroj: Journal of Hepatology
ISSN: 0168-8278
DOI: 10.1016/j.jhep.2017.02.014
Popis: Background: Carriers of the transmembrane 6 superfamily member 2 E167K gene variant (TM6SF2(EK/KK)) have decreased expression of the TM6SF2 gene and increased risk of NAFLD and NASH. Unlike common 'obese/metabolic' NAFLD, these subjects lack hypertriglyceridemia and have lower risk of cardiovascular disease. In animals, phosphatidylcholine (PC) deficiency results in a similar phenotype. PCs surround the core of VLDL consisting of triglycerides (TGs) and cholesteryl-esters (CEs). We determined the effect of the TM6SF2 E167K on these lipids in the human liver and serum and on hepatic gene expression and studied the effect of TM6SF2 knockdown on hepatocyte handling of these lipids. Methods: Liver biopsies were taken from subjects characterized with respect to the TM6SF2 genotype, serum and liver lipidome, gene expression and histology. In vitro, after TM6SF2 knockdown in HuH-7 cells, we compared incorporation of different fatty acids into TGs, CEs, and PCs. Results: The TM6SF2(EK/KK) and TM6SF2EE groups had similar age, gender, BMI and HOMA-IR. Liver TGs and CEs were higher and liver PCs lower in the TM6SF2(EK/KK) than the TM6SF2EE group (p Conclusions: Hepatic lipid synthesis from PUFAs is impaired and could contribute to deficiency in PCs and increased intrahepatic TG in TM6SF2 E167K variant carriers. (C) 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Databáze: OpenAIRE
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