GRP78 rescues the ABCG5 ABCG8 sterol transporter in db/db mice

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• 作者：Yuhuan Wangp>ap> ; Kai Sup>ap> ; Nadezhda S. Sabevap>ep> ; Ailing Jip>cp>p> ; p>p>dp> ; Deneys R. van der Westhuyzenp>bp>p> ; p>p>cp>p> ; p>p>dp> ; Fabienne Foufellep>fp> ; Xia Gaop>gp> ; Gregory A. Grafp>ap>p> ; p>p>bp>p> ; p>p>Gregory.Graf@uky.edu" class="auth_mail" title="E-mail the corresponding authorp>
• 关键词：G5G8 ; ABCG5 ABCG8 ; ACC1 ; acetyl-CoA carboxylase ; AdGRP78 ; adenoviral vector encoding GRP78 ; AdCre ; adenoviral vector encoding Cre-recombinase ; FOXO1 ; forkhead box O1A ; ER ; endoplasmic reticulum ; eiF2伪 ; eukaryotic translation initiation factor 2伪 ; AdEmpty ; empty adenoviral vector ; FAS ; fatty acid synthase ; GRP78 ; glucose regulated protein 78-kDa ; GWAS ; genome-wide association study ; HF ; high fat ; HNF4伪 ; hepatic nuclear receptor 4 伪 ; HV ; hepatic vagotomy ; KO ; knockout ; ob/ob ; leptin deficient mice
• 刊名：Metabolism
• 出版年：2015
• 出版时间：November 2015
• 年：2015
• 卷：64
• 期：11
• 页码：1435-1443
• 全文大小：764 K

文摘

Mice lacking leptin (ob/ob) or its receptor (db/db) are obese, insulin resistant, and have reduced levels of biliary cholesterol due, in part, to reduced levels of hepatic G5G8. Chronic leptin replacement restores G5G8 abundance and increases biliary cholesterol concentrations, but the molecular mechanisms responsible for G5G8 regulation remain unclear. In the current study, we used a series of mouse models to address potential mechanisms for leptin-mediated regulation of G5G8.p>

Methods and Results

<p id="sp0010">We acutely replaced leptin in ob/ob mice and deleted hepatic leptin receptors in lean mice. Neither manipulation altered G5G8 abundance or biliary cholesterol. Similarly, hepatic vagotomy had no effect on G5G8. Alternatively, G5G8 may be decreased in ob/ob and db/db mice due to ER dysfunction, the site of G5G8 complex assembly. Overexpression of the ER chaperone GRP78 using an adenoviral vector restores ER function and reduces steatosis in ob/ob mice. Therefore, we determined if AdGRP78 could rescue G5G8 in db/db mice. As in ob/ob mice, AdGRP78 reduced expression of lipogenic genes and plasma triglycerides in the db/db strain. Both G5 and G8 protein levels increased as did total biliary cholesterol, but in the absence of changes in G5 or G8 mRNAs. The increase in G5G8 was associated with increases in a number of proteins, including the ER lectin chaperone, calnexin, a key regulator of G5G8 complex assembly.p>

Conclusions

<p id="sp0015">Leptin signaling does not directly regulate G5G8 abundance. The loss of G5G8 in mice harboring defects in the leptin axis is likely associated with compromised ER function.