Depletion of TM6SF2 disturbs membrane lipid composition and dynamics in HuH7 hepatoma cells.
A polymorphism of TM6SF2 associates with hepatic lipid accumulation and reduction of triacylglycerol (TAG) secretion, but the function of the encoded protein has remained enigmatic. We studied the effect of stable TM6SF2 knock-down on the lipid content and composition, mitochondrial fatty acid oxidation and organelle structure of HuH7 hepatoma cells. Knock-down of TM6SF2 resulted in intracellular accumulation of TAGs, cholesterol esters, phosphatidylcholine (PC) and phosphatidylethanolamine. In all of these lipid classes, polyunsaturated lipid species were significantly reduced while saturated and monounsaturated species increased their proportions. The PCs encountered relative and absolute arachidonic acid (AA, 20:4n-6) depletion, and AA was also reduced in the total cellular fatty acid pool. Synthesis and turnover of the hepatocellular glycerolipids was enhanced. The TM6SF2 knock-down cells secreted lipoprotein-like particles with a smaller diameter than in the controls, and more lysosome/endosome structures appeared in the knock-down cells. The mitochondrial capacity for palmitate oxidation was significantly reduced. These observations provide novel clues to TM6SF2 function and raise altered mebrane lipid composition and dynamics among the mechanism(s) by which the protein deficiency disturbs hepatic TAG secretion.
['Ruhanen|Hanna|H|', 'Nidhina Haridas|P A|PA|', 'Eskelinen|Eeva-Liisa|EL|', 'Eriksson|Ove|O|', 'Olkkonen|Vesa M|VM|', 'Käkelä|Reijo|R|']
D016718:Arachidonic Acid D006528:Carcinoma, Hepatocellular D045744:Cell Line, Tumor D002788:Cholesterol Esters D011992:Endosomes D005227:Fatty Acids D055785:Gene Knockdown Techniques D022781:Hepatocytes D006801:Humans D050356:Lipid Metabolism D008074:Lipoproteins D008113:Liver Neoplasms D008247:Lysosomes D008563:Membrane Lipids D008565:Membrane Proteins D010084:Oxidation-Reduction D010713:Phosphatidylcholines D010714:Phosphatidylethanolamines D014280:Triglycerides
TM6SF2 Triacylglycerol Fatty acid oxidation Phosphatidylcholine Arachidonic acid Lipidome