title: Lepr(db/db) Mice with senescence marker protein-30 knockout (Lepr(db/db)Smp30(Y/-)) exhibit increases in small dense-LDL and severe fatty liver despite being fed a standard diet.
abstract: OBJECTIVE
  The senescence marker protein-30 (SMP30) is a 34 kDa protein originally identified in rat liver that shows decreased levels with age. Several functional studies using SMP30 knockout (Smp30(Y/-) ) mice established that SMP30 functions as an antioxidant and protects against apoptosis. To address the potential role of SMP30 in nonalcoholic fatty liver disease (NAFLD) pathogenesis, we established Smp30(Y/-) mice on a Lepr(db/db) background (Lepr(db/db)Smp30(Y/-) mice). RESEARCH DESIGN/PRINCIPAL FINDINGS: Male Lepr(db/db)Smp30(Y/-) mice were fed a standard diet (340 kcal/100 g, fat 5.6%) for 16 weeks whereupon the lipid/lipoprotein profiles, hepatic expression of genes related to lipid metabolism and endoplasmic reticulum stress markers were analyzed by HPLC, quantitative RT-PCR and western blotting, respectively. Changes in the liver at a histological level were also investigated. The amount of SMP30 mRNA and protein in livers was decreased in Lepr(db/db)Smp30(Y/+) mice compared with Lepr(db/+)Smp30(Y/+) mice. Compared with Lepr(db/db)Smp30(Y/+) mice, 24 week old Lepr(db/db)Smp30(Y/-) mice showed: i) increased small dense LDL-cho and decreased HDL-cho levels; ii) fatty liver accompanied by numerous inflammatory cells and increased oxidative stress; iii) decreased mRNA expression of genes involved in fatty acid oxidation (PPARα) and lipoprotein uptake (LDLR and VLDLR) but increased CD36 levels; and iv) increased endoplasmic reticulum stress.
  
  
  CONCLUSIONS
  Our data strongly suggest that SMP30 is closely associated with NAFLD pathogenesis, and might be a possible therapeutic target for NAFLD.
authors.affiliation: Molecular Regulation of Aging, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Kondo
authors.forename: Goji
authors.initials: G
authors.lastname: Hasegawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Okada
authors.forename: Takafumi
authors.initials: T
authors.lastname: Senmaru
authors.forename: Michiaki
authors.initials: M
authors.lastname: Fukui
authors.forename: Naoto
authors.initials: N
authors.lastname: Nakamura
authors.forename: Morio
authors.initials: M
authors.lastname: Sawada
authors.forename: Jo
authors.initials: J
authors.lastname: Kitawaki
authors.forename: Takeshi
authors.initials: T
authors.lastname: Okanoue
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kishimoto
authors.forename: Akiko
authors.initials: A
authors.lastname: Amano
authors.forename: Naoki
authors.initials: N
authors.lastname: Maruyama
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Obayashi
authors.forename: Akihito
authors.initials: A
authors.lastname: Ishigami
mesh_terms: D000818:Animals; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000172:deficiency / Q000235:genetics*; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D059305:Diet, High-Fat / Q000009:adverse effects; D004041:Dietary Fats / Q000008:administration & dosage; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D005786:Gene Expression Regulation; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics*; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism; D012720:Severity of Illness Index; D015398:Signal Transduction
chemical_list: D018955:CD36 Antigens; D002135:Calcium-Binding Proteins; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D004041:Dietary Fats; D047908:Intracellular Signaling Peptides and Proteins; D047493:PPAR alpha; D011973:Receptors, LDL; D054411:Receptors, Leptin; C513324:Rgn protein, mouse; C036053:VLDL receptor; C515447:leptin receptor, mouse