Research Articles
Hepatic trans-Golgi action coordinated by the GTPase ARFRP1 is crucial for lipoprotein lipidation and assembly

https://doi.org/10.1194/jlr.M040089Get rights and content
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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 (Arfrp1liv−/−) 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 Arfrp1liv−/− mice but accumulates in the liver accompanied by elevated triglycerides. Fractionation of Arfrp1liv−/− 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.

ADP-ribosylation factor-related protein 1
very low density lipoprotein
high density lipoprotein
apolipoprotein B
apolipoprotein A1
apolipoprotein C3
guanosine triphosphatase

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This work was supported by the German Research Foundation (DFG; SFB 958) and the German Ministry of Education and Research (BMBF: DZD, 01GI0922) and the State of Brandenburg.

The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of three figures.

    Abbreviations:

    ARFRP1

    ADP-ribosylation factor-related protein 1

    Arfrp1liv−/−

    liver-specific Arfrp1-knockout

    ER

    endoplasmic reticulum

    FPLC

    fast-protein liquid chromatography

    GTPase

    guanosine triphosphatase

    IHC

    immunohistochemical

    MTP

    microsomal triglyceride-transfer protein

    WB

    Western blot