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

Abstract

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.

Involvement of senescence marker protein‐30 in glucose metabolism disorder and non‐alcoholic fatty liver disease

“…Eight‐week‐old Lepr db/db Smp30 Y/− male mice were given vitamin C‐supplemented water and a standard diet (340 kcal/100 g, fat 5.6%) for 16 weeks. We found, first, that hepatic SMP30 mRNA and protein levels in Lepr db/db Smp30 Y+ were significantly lower than in Lepr db/+ Smp30 Y/+ mice, suggesting that the SMP30 level is affected by overeating‐induced obesity and obesity‐related diseases . We also reported that hepatic SMP30 mRNA levels were significantly lower in C57BL/6CrSlc female mice fed a diet of highly saturated fatty acids (60% fat) for 8 weeks compared with recipients of a normal diet (4.5% fat) .…”

“…Lepr db/db Smp30 Y/− mice showed increases of small, dense LDL‐cholesterol content, but a decrease of high‐density lipoprotein cholesterol levels compared with Lepr db/db Smp30 Y/+ mice, although plasma levels of total cholesterol were similar in both strains (Fig. ) . The quantitative reverse transcription polymerase chain reaction analysis showed that amounts of hepatic LDL and VLDL receptor mRNA were significantly lower in Lepr db/db Smp30 Y/− mice than those of Lepr db/db Smp30 Y/+ mice .…”

“…) . Accordingly, gene expression of CD36, a member of the class B scavenger receptor family of cell surface protein that is expressed in monocytes/macrophages, was upregulated in Lepr db/db Smp30 Y/− mice compared with Lepr db/db Smp30 Y/+ mice, suggesting the infiltration of monocytes/macrophages into the livers …”

The Role of Senescence in the Development of Nonalcoholic Fatty Liver Disease and Progression to Nonalcoholic Steatohepatitis

“…Both SMP‐30‐knockout mice on a Lepr db/db background as well as SMP30/superoxide dismutase‐1 double‐knockout mice developed hepatic steatosis and presented higher levels of hepatic oxidative stress and superoxide anion radicals compared with WT mice. These findings were attributed to decreased levels of hepatic apolipoprotein B and transcription factors involved in lipid metabolism . Similarly, NASH induction by methionine and choline‐deficient diet into p53‐deficient male mice resulted in slower disease progression accompanied by lower ROS accumulation and lipid peroxidation as well as fewer apoptotic cells compared with the WT mice .…”

Anti-inflammatory activity of SMP30 modulates NF-κB through protein tyrosine kinase/phosphatase balance

“…The functional activities of SMP30 include its involvement in intracellular calcium pumping [5], cell-to-cell junction formation [6], organophosphatase activity [7], and lactonase activity in relation to vitamin C biosynthesis in rodents [8]. Interestingly, it has been reported that SMP30-deficient mice are more susceptible to UV-or cigarette-smoke-induced stress and that they are vulnerable to lung diseases, such as emphysema [9,10], hepatic hyperlipidemic diseases [11,12], cataract formation [13], and pancreatic insulin-release problems [14]. In addition, the finding of the upregulation of oxidative stressrelated protein carbonyls in the lung of the SMP30 knockout mouse further expanded physiological roles for SMP30 [10].…”