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

Luukkonen, Panu K.; Zhou, You; Nidhina Haridas, P. A.; Dwivedi, Om P.; Hyötyläinen, Tuulia; Ali, Ashfaq; Juuti, Anne; Leivonen, Marja; Tukiainen, Taru and Ahonen, Linda, et al. (2017) In Journal of Hepatology 67(1). p.128-136
Abstract

Background: Carriers of the transmembrane 6 superfamily member 2 E167K gene variant (TM6SF2EK/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... (More)

Background: Carriers of the transmembrane 6 superfamily member 2 E167K gene variant (TM6SF2EK/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 TM6SF2EK/KK and TM6SF2EE groups had similar age, gender, BMI and HOMA-IR. Liver TGs and CEs were higher and liver PCs lower in the TM6SF2EK/KK than the TM6SF2EE group (p <0.05). Polyunsaturated fatty acids (PUFA) were deficient in liver and serum TGs and liver PCs but hepatic free fatty acids were relatively enriched in PUFA (p <0.05). Incorporation of PUFA into TGs and PCs in TM6SF2 knockdown hepatocytes was decreased (p <0.05). Hepatic expression of TM6SF2 was decreased in variant carriers, and was co-expressed with genes regulated by PUFAs. Conclusions: Hepatic lipid synthesis from PUFAs is impaired and could contribute to deficiency in PCs and increased intrahepatic TG in TM6SF2 E167K variant carriers.

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@article{29023508-073c-445f-9807-b0c36acb9e8f,
  abstract     = {<p>Background: Carriers of the transmembrane 6 superfamily member 2 E167K gene variant (TM6SF2<sup>EK/KK</sup>) 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<sup>EK/KK</sup> and TM6SF2<sup>EE</sup> groups had similar age, gender, BMI and HOMA-IR. Liver TGs and CEs were higher and liver PCs lower in the TM6SF2<sup>EK/KK</sup> than the TM6SF2<sup>EE</sup> group (p &lt;0.05). Polyunsaturated fatty acids (PUFA) were deficient in liver and serum TGs and liver PCs but hepatic free fatty acids were relatively enriched in PUFA (p &lt;0.05). Incorporation of PUFA into TGs and PCs in TM6SF2 knockdown hepatocytes was decreased (p &lt;0.05). Hepatic expression of TM6SF2 was decreased in variant carriers, and was co-expressed with genes regulated by PUFAs. Conclusions: Hepatic lipid synthesis from PUFAs is impaired and could contribute to deficiency in PCs and increased intrahepatic TG in TM6SF2 E167K variant carriers.</p>},
  author       = {Luukkonen, Panu K. and Zhou, You and Nidhina Haridas, P. A. and Dwivedi, Om P. and Hyötyläinen, Tuulia and Ali, Ashfaq and Juuti, Anne and Leivonen, Marja and Tukiainen, Taru and Ahonen, Linda and Scott, Emma and Palmer, Jeremy M. and Arola, Johanna and Orho-Melander, Marju and Vikman, Petter and Anstee, Quentin M. and Olkkonen, Vesa M. and Orešič, Matej and Groop, Leif and Yki-Järvinen, Hannele},
  issn         = {0168-8278},
  keyword      = {Arachidonic acid,Cholesterol esters,Fatty acids,Genotype,Hepatocytes,Lipogenesis,Non-alcoholic fatty liver disease,Phosphatidylcholines,Transmembrane 6 superfamily member 2,Triglycerides},
  language     = {eng},
  number       = {1},
  pages        = {128--136},
  publisher    = {Elsevier},
  series       = {Journal of Hepatology},
  title        = {Impaired hepatic lipid synthesis from polyunsaturated fatty acids in TM6SF2 E167K variant carriers with NAFLD},
  url          = {http://dx.doi.org/10.1016/j.jhep.2017.02.014},
  volume       = {67},
  year         = {2017},
}