title: Hepatocyte-Specific Depletion of UBXD8 Induces Periportal Steatosis in Mice Fed a High-Fat Diet.
abstract: We showed previously that UBXD8 plays a key role in proteasomal degradation of lipidated ApoB in hepatocarcinoma cell lines. In the present study, we aimed to investigate the functions of UBXD8 in liver in vivo. For this purpose, hepatocyte-specific UBXD8 knockout (UBXD8-LKO) mice were generated. They were fed with a normal or high-fat diet, and the phenotypes were compared with those of littermate control mice. Hepatocytes obtained from UBXD8-LKO and control mice were analyzed in culture. After 26 wk of a high-fat diet, UBXD8-LKO mice exhibited macrovesicular steatosis in the periportal area and microvesicular steatosis in the perivenular area, whereas control mice exhibited steatosis only in the perivenular area. Furthermore, UBXD8-LKO mice on a high-fat diet had significantly lower concentrations of serum triglyceride and VLDL than control mice. A Triton WR-1339 injection study revealed that VLDL secretion from hepatocytes was reduced in UBXD8-LKO mice. The decrease of ApoB secretion upon UBXD8 depletion was recapitulated in cultured primary hepatocytes. Accumulation of lipidated ApoB in lipid droplets was observed only in UBXD8-null hepatocytes. The results showed that depletion of UBXD8 in hepatocytes suppresses VLDL secretion, and could lead to periportal steatosis when mice are fed a high-fat diet. This is the first demonstration that an abnormality in the intracellular ApoB degradation mechanism can cause steatosis, and provides a useful model for periportal steatosis, which occurs in several human diseases.
authors.affiliation: Department of Anatomy and Molecular Cell Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Norihiro
authors.initials: N
authors.lastname: Imai
authors.affiliation: Department of Anatomy and Molecular Cell Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Michitaka
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Hayashi
authors.affiliation: Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Ishigami
authors.affiliation: Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Hirooka
authors.affiliation: Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, Kobe, Japan.
authors.forename: Takaya
authors.initials: T
authors.lastname: Abe
authors.affiliation: Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, Kobe, Japan.
authors.forename: Go
authors.initials: G
authors.lastname: Shioi
authors.affiliation: Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Hidemi
authors.initials: H
authors.lastname: Goto
authors.affiliation: Department of Anatomy and Molecular Cell Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Toyoshi
authors.initials: T
authors.lastname: Fujimoto
mesh_terms: D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism; D001798:Blood Proteins / Q000502:physiology*; D059305:Diet, High-Fat / Q000009:adverse effects*; D005234:Fatty Liver / Q000209:etiology / Q000378:metabolism*; D005260:Female; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008079:Lipoproteins, VLDL / Q000097:blood; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000502:physiology*; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D014280:Triglycerides / Q000378:metabolism
chemical_list: D001055:Apolipoproteins B; D001798:Blood Proteins; D008079:Lipoproteins, VLDL; D008565:Membrane Proteins; D014280:Triglycerides; C000605074:UBXD8 protein, mouse; D000469:Alkaline Phosphatase