title: TM6SF2 rs58542926 impacts lipid processing in liver and small intestine.
abstract: The transmembrane 6 superfamily member 2 (TM6SF2) loss-of-function variant rs58542926 is a genetic risk factor for nonalcoholic fatty liver disease and progression to fibrosis but is paradoxically associated with lower levels of hepatically derived triglyceride-rich lipoproteins. TM6SF2 is expressed predominantly in liver and small intestine, sites for triglyceride-rich lipoprotein biogenesis and export. In light of this, we hypothesized that TM6SF2 may exhibit analogous effects on both liver and intestine lipid homeostasis. To test this, we genotyped rs58542926 in 983 bariatric surgery patients from the Geisinger Medical Center for Nutrition and Weight Management, Geisinger Health System, in Pennsylvania and from 3,556 study participants enrolled in the Amish Complex Disease Research Program. Although these two cohorts have different metabolic profiles, carriers in both cohorts had improved fasting lipid profiles. Importantly, following a high-fat challenge, carriers in the Amish Complex Disease Research Program cohort exhibited significantly lower postprandial serum triglycerides, suggestive of a role for TM6SF2 in the small intestine. To gain further insight into this putative role, effects of TM6SF2 deficiency were studied in a zebrafish model and in cultured human Caco-2 enterocytes. In both systems TM6SF2 deficiency resulted in defects in small intestine metabolism in response to dietary lipids, including significantly increased lipid accumulation, decreased lipid clearance, and increased endoplasmic reticulum stress.
  
  
  
  These data strongly support a role of TM6SF2 in the regulation of postprandial lipemia, potentially through a similar function for TM6SF2 in the lipidation and/or export of both hepatically and intestinally derived triglyceride-rich lipoproteins. (Hepatology 2017;65:1526-1542).
authors.affiliation: Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: O'Hare
authors.affiliation: Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Rongze
authors.initials: R
authors.lastname: Yang
authors.affiliation: Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Yerges-Armstrong
authors.affiliation: Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Urmila
authors.initials: U
authors.lastname: Sreenivasan
authors.affiliation: Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Rebecca
authors.initials: R
authors.lastname: McFarland
authors.affiliation: Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Carmen C
authors.initials: CC
authors.lastname: Leitch
authors.affiliation: Department of Embryology, Carnegie Institution for Science, Baltimore, MD.
authors.forename: Meredith H
authors.initials: MH
authors.lastname: Wilson
authors.affiliation: Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Shilpa
authors.initials: S
authors.lastname: Narina
authors.affiliation: Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Alexis
authors.initials: A
authors.lastname: Gorden
authors.affiliation: Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Kathy A
authors.initials: KA
authors.lastname: Ryan
authors.affiliation: Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Shuldiner
authors.affiliation: Department of Embryology, Carnegie Institution for Science, Baltimore, MD.
authors.forename: Steve A
authors.initials: SA
authors.lastname: Farber
authors.affiliation: Geisinger Clinic, Geisinger Obesity Research Institute, Danville, PA.
authors.forename: G Craig
authors.initials: GC
authors.lastname: Wood
authors.affiliation: Department of Medical Genetics and Biochemistry, Temple University School of Medicine, Philadelphia, PA.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Still
authors.affiliation: Geisinger Clinic, Geisinger Obesity Research Institute, Danville, PA.|Department of Medical Genetics and Biochemistry, Temple University School of Medicine, Philadelphia, PA.
authors.forename: Glenn S
authors.initials: GS
authors.lastname: Gerhard
authors.affiliation: Geisinger Clinic, Geisinger Obesity Research Institute, Danville, PA.
authors.forename: Janet D
authors.initials: JD
authors.lastname: Robishaw
authors.affiliation: Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD.|Baltimore VA Medical Center, VA Research Service, Geriatric Research, Education and Clinical Center and VA Maryland Health Care System, Baltimore, MD.
authors.forename: Carole
authors.initials: C
authors.lastname: Sztalryd
authors.affiliation: Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Norann A
authors.initials: NA
authors.lastname: Zaghloul
mesh_terms: D000818:Animals; D001483:Base Sequence; D018938:Caco-2 Cells; D059865:Endoplasmic Reticulum Stress; D020895:Enterocytes / Q000378:metabolism; D005234:Fatty Liver / Q000235:genetics; D005260:Female; D022781:Hepatocytes / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007421:Intestine, Small / Q000378:metabolism* / Q000648:ultrastructure; D050356:Lipid Metabolism / Q000235:genetics*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D019518:Postprandial Period; D014280:Triglycerides / Q000096:biosynthesis / Q000097:blood; D014415:Tunicamycin; D015027:Zebrafish
chemical_list: D008565:Membrane Proteins; C419195:TM6SF2 protein, human; D014280:Triglycerides; D014415:Tunicamycin