title: Hepatic trans-Golgi action coordinated by the GTPase ARFRP1 is crucial for lipoprotein lipidation and assembly.
abstract: The liver is a major organ in whole body lipid metabolism and malfunctioning can lead to various diseases including dyslipidemia, fatty liver disease, and type 2 diabetes. Triglycerides and cholesteryl esters are packed in the liver as very low density lipoproteins (VLDLs). Generation of these lipoproteins is initiated in the endoplasmic reticulum and further maturation likely occurs in the Golgi. ADP-ribosylation factor-related protein 1 (ARFRP1) is a small trans-Golgi-associated guanosine triphosphatase (GTPase) that regulates protein sorting and is required for chylomicron lipidation and assembly in the intestine. Here we show that the hepatocyte-specific deletion of Arfrp1 (Arfrp1(liv-/-)) results in impaired VLDL lipidation leading to reduced plasma triglyceride levels in the fasted state as well as after inhibition of lipoprotein lipase activity by Triton WR-1339. In addition, the concentration of ApoC3 that comprises 40% of protein mass of secreted VLDLs is markedly reduced in the plasma of Arfrp1(liv-/-) mice but accumulates in the liver accompanied by elevated triglycerides. Fractionation of Arfrp1(liv-/-) liver homogenates reveals more ApoB48 and a lower concentration of triglycerides in the Golgi compartments than in the corresponding fractions from control livers. In conclusion, ARFRP1 and the Golgi apparatus play an important role in lipoprotein maturation in the liver by influencing lipidation and assembly of proteins to the lipid particles.
authors.affiliation: Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke, D-14558 Nuthetal, Germany.
authors.forename: Deike
authors.initials: D
authors.lastname: Hesse
authors.forename: Katrin
authors.initials: K
authors.lastname: Radloff
authors.forename: Alexander
authors.initials: A
authors.lastname: Jaschke
authors.forename: Merit
authors.initials: M
authors.lastname: Lagerpusch
authors.forename: Bomee
authors.initials: B
authors.lastname: Chung
authors.forename: Anne
authors.initials: A
authors.lastname: Tailleux
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.forename: Annette
authors.initials: A
authors.lastname: Schürmann
mesh_terms: D020727:ADP-Ribosylation Factors / Q000502:physiology*; D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism; D004721:Endoplasmic Reticulum; D050155:Lipogenesis; D008075:Lipoproteins, HDL / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011499:Protein Processing, Post-Translational; D014280:Triglycerides / Q000378:metabolism; D021601:trans-Golgi Network / Q000201:enzymology* / Q000378:metabolism*
chemical_list: D016632:Apolipoprotein A-I; D008075:Lipoproteins, HDL; D008079:Lipoproteins, VLDL; D014280:Triglycerides; D020727:ADP-Ribosylation Factors; C531986:Arfrp1 protein, mouse
keywords: ADP-ribosylation factor-related protein 1; apolipoprotein A1; apolipoprotein B; apolipoprotein C3; guanosine triphosphatase; high density lipoprotein; very low density lipoprotein