title: The Genetic Variant I148M in PNPLA3 Is Associated With Increased Hepatic Retinyl-Palmitate Storage in Humans.
abstract: BACKGROUND
  Previous studies revealed that the common sequence variant I148M in patatin-like phospholipase domain-containing protein 3 (PNPLA3) is associated with liver fat content and liver diseases, but not with insulin resistance. Recent data suggest that the PNPLA3 I148M variant has reduced retinyl-palmitate lipase activity in hepatic stellate cells.
  
  
  OBJECTIVE
  We hypothesized that the PNPLA3 I148M variant is associated with elevated retinyl-palmitate storage in human liver as a potential link to the clinical pathology. Design/Setting and Participants: Using HPLC, we quantified the retinoid metabolites in liver tissue extracts obtained from 42 human subjects, including 13 heterozygous and six homozygous carriers of the minor PNPLA3 I148M variant.
  
  
  METHODS
  Retinyl-palmitate is elevated in human livers of homozygous PNPLA3 I148M allele carriers Results: The PNPLA3 I148M variant was associated with a significant increase (1.4-fold) in liver fat. The content of retinyl-palmitate was elevated and the ratio of retinol/retinyl-palmitate was reduced in liver extracts obtained from homozygous PNPLA3 I148M minor allele carriers. In a multivariate model including liver fat content, these differences remained significant independent of liver fat content. The content of the minor retinyl-fatty acid esters was similarly increased in homozygous PNPLA3 I148M carriers.
  
  
  CONCLUSIONS
  The increased content of hepatic retinyl-palmitate and the reduced ratio of retinol/retinyl-palmitate in PNPLA3 I148M minor allele carriers support in vitro findings of an altered retinyl-palmitate lipase activity. Our results indicate that the PNPLA3 I148M variant is relevant for the retinyl-palmitate content in human liver, providing a possible link to chronic liver disease.
authors.affiliation: Department of Internal Medicine (M.K., F.M., H.-U.H., E.S., A.P.), Division of Endocrinology, Diabetology, Angiology, Nephrology, Clinical Chemistry and Pathobiochemistry, University of Tübingen, 72076 Tübingen, Germany; Department of General, Visceral and Transplant Surgery (I.K., A.K.), University of Tübingen, 72076 Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen (F.M., H.-U.H., E.S., A.P.), 72076 Tübingen, Germany; and German Center for Diabetes Research (DZD) (F.M., H.-U.H., E.S., A.P.), 85764 München-Neuherberg, Germany.
authors.forename: Marketa
authors.initials: M
authors.lastname: Kovarova
authors.affiliation: Department of Internal Medicine (M.K., F.M., H.-U.H., E.S., A.P.), Division of Endocrinology, Diabetology, Angiology, Nephrology, Clinical Chemistry and Pathobiochemistry, University of Tübingen, 72076 Tübingen, Germany; Department of General, Visceral and Transplant Surgery (I.K., A.K.), University of Tübingen, 72076 Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen (F.M., H.-U.H., E.S., A.P.), 72076 Tübingen, Germany; and German Center for Diabetes Research (DZD) (F.M., H.-U.H., E.S., A.P.), 85764 München-Neuherberg, Germany.
authors.forename: Ingmar
authors.initials: I
authors.lastname: Königsrainer
authors.affiliation: Department of Internal Medicine (M.K., F.M., H.-U.H., E.S., A.P.), Division of Endocrinology, Diabetology, Angiology, Nephrology, Clinical Chemistry and Pathobiochemistry, University of Tübingen, 72076 Tübingen, Germany; Department of General, Visceral and Transplant Surgery (I.K., A.K.), University of Tübingen, 72076 Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen (F.M., H.-U.H., E.S., A.P.), 72076 Tübingen, Germany; and German Center for Diabetes Research (DZD) (F.M., H.-U.H., E.S., A.P.), 85764 München-Neuherberg, Germany.
authors.forename: Alfred
authors.initials: A
authors.lastname: Königsrainer
authors.affiliation: Department of Internal Medicine (M.K., F.M., H.-U.H., E.S., A.P.), Division of Endocrinology, Diabetology, Angiology, Nephrology, Clinical Chemistry and Pathobiochemistry, University of Tübingen, 72076 Tübingen, Germany; Department of General, Visceral and Transplant Surgery (I.K., A.K.), University of Tübingen, 72076 Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen (F.M., H.-U.H., E.S., A.P.), 72076 Tübingen, Germany; and German Center for Diabetes Research (DZD) (F.M., H.-U.H., E.S., A.P.), 85764 München-Neuherberg, Germany.
authors.forename: Fausto
authors.initials: F
authors.lastname: Machicao
authors.affiliation: Department of Internal Medicine (M.K., F.M., H.-U.H., E.S., A.P.), Division of Endocrinology, Diabetology, Angiology, Nephrology, Clinical Chemistry and Pathobiochemistry, University of Tübingen, 72076 Tübingen, Germany; Department of General, Visceral and Transplant Surgery (I.K., A.K.), University of Tübingen, 72076 Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen (F.M., H.-U.H., E.S., A.P.), 72076 Tübingen, Germany; and German Center for Diabetes Research (DZD) (F.M., H.-U.H., E.S., A.P.), 85764 München-Neuherberg, Germany.
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Häring
authors.affiliation: Department of Internal Medicine (M.K., F.M., H.-U.H., E.S., A.P.), Division of Endocrinology, Diabetology, Angiology, Nephrology, Clinical Chemistry and Pathobiochemistry, University of Tübingen, 72076 Tübingen, Germany; Department of General, Visceral and Transplant Surgery (I.K., A.K.), University of Tübingen, 72076 Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen (F.M., H.-U.H., E.S., A.P.), 72076 Tübingen, Germany; and German Center for Diabetes Research (DZD) (F.M., H.-U.H., E.S., A.P.), 85764 München-Neuherberg, Germany.
authors.forename: Erwin
authors.initials: E
authors.lastname: Schleicher
authors.affiliation: Department of Internal Medicine (M.K., F.M., H.-U.H., E.S., A.P.), Division of Endocrinology, Diabetology, Angiology, Nephrology, Clinical Chemistry and Pathobiochemistry, University of Tübingen, 72076 Tübingen, Germany; Department of General, Visceral and Transplant Surgery (I.K., A.K.), University of Tübingen, 72076 Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen (F.M., H.-U.H., E.S., A.P.), 72076 Tübingen, Germany; and German Center for Diabetes Research (DZD) (F.M., H.-U.H., E.S., A.P.), 85764 München-Neuherberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Peter
mesh_terms: D000368:Aged; D000483:Alleles; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008049:Lipase / Q000235:genetics*; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D010168:Palmitates / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D012176:Retinoids / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism; D014801:Vitamin A / Q000378:metabolism; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
chemical_list: D005227:Fatty Acids; D008049:Lipase; D008565:Membrane Proteins; D010168:Palmitates; D012176:Retinoids; D014280:Triglycerides; D014801:Vitamin A; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent