Leprdb/db Mice with Senescence Marker Protein-30 Knockout (Leprdb/dbSmp30Y/−) Exhibit Increases in Small Dense-LDL and Severe Fatty Liver Despite Being Fed a Standard Diet

Yoshitaka Kondo,Naoki Maruyama,Takafumi Senmaru,Hiroshi Okada,Takeshi Okanoue,Goji Hasegawa,Michiaki Fukui,Naoto Nakamura,Hiroshi Obayashi,Akihito Ishigami,Yuki Kishimoto,Morio Sawada,Akiko Amano,Jo Kitawaki

doi:10.1371/journal.pone.0065698

Yoshitaka Kondo, Naoki Maruyama + Show 12 more

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https://doi.org/10.1371/journal.pone.0065698

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Background/AimsThe 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 (Smp30Y/−) 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 Smp30Y/− mice on a Leprdb/db background (Leprdb/dbSmp30Y/− mice).Research Design/Principal FindingsMale Leprdb/dbSmp30Y/− 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 Leprdb/dbSmp30Y/+ mice compared with Leprdb/+Smp30Y/+ mice. Compared with Leprdb/dbSmp30Y/+ mice, 24 week old Leprdb/dbSmp30Y/− 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.ConclusionOur data strongly suggest that SMP30 is closely associated with NAFLD pathogenesis, and might be a possible therapeutic target for NAFLD.

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Metabolic syndrome has been described as the association of insulin resistance, hypertension, hyperlipidemia and obesity
Our data strongly suggest that senescence marker protein-30 (SMP30) is closely associated with nonalcoholic fatty liver disease (NAFLD) pathogenesis, and might be a possible therapeutic target for NAFLD
Generation of Leprdb/dbSmp30Y/2 mice As shown in Fig. 1A and B, we established Leprdb/dbSmp30Y/2 mice, which were born at the expected Mendelian ratios and by 24 weeks of age had appearances that were indistinguishable from obese Leprdb/dbSmp30Y/+ mice

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Introduction

Metabolic syndrome has been described as the association of insulin resistance, hypertension, hyperlipidemia and obesity. Its prevalence has increased dramatically, mainly in developed countries. The hepatic manifestations of metabolic syndrome include nonalcoholic fatty liver disease (NAFLD) and its progressive variant, nonalcoholic steatohepatitis (NASH) [1,2]. Several animal models have been proposed for NAFLD and NASH research [3]. Since leptin plays a major role in food intake and energy expenditure, total leptin deficiency or leptin resistance can lead to massive obesity, type 2 diabetes, dyslipidemia and fatty liver.

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