Nonalcoholic fatty liver disease (NAFLD) is characterized by a massive accumulation of lipid droplets (LDs). The aim of this study was to determine the function of 17β-hydroxysteroid dehydrogenase-13 (17β-HSD13), one of our newly identified LD-associated proteins in human subjects with normal liver histology and simple steatosis, in NAFLD development. LDs were isolated from 21 human liver biopsies, including 9 cases with normal liver histology (group 1) and 12 cases with simple steatosis (group 2). A complete set of LD-associated proteins from three liver samples of group 1 or group 2 were determined by 2D LC-MS/MS. By comparing the LD-associated protein profiles between subjects with or without NAFLD, 54 up-regulated and 35 down-regulated LD-associated proteins were found in NAFLD patients. Among them, 17β-HSD13 represents a previously unidentified LD-associated protein with a significant up-regulation in NAFLD. Because the 17β-HSD family plays an important role in lipid metabolism, 17β-HSD13 was selected for validating the proteomic findings and exploring its role in the pathogenesis of NAFLD. Increased hepatic 17β-HSD13 and its LD surface location were confirmed in db/db (diabetic) and high-fat diet-fed mice. Adenovirusmediated hepatic overexpression of human 17β-HSD13 induced a fatty liver phenotype in C57BL/6 mice, with a significant increase in mature sterol regulatory element-binding protein 1 and fatty acid synthase levels. The present study reports an extensive set of human liver LD proteins and an array of proteins differentially expressed in human NAFLD. We also identified 17β-HSD13 as a pathogenic protein in the development of NAFLD.lipogenesis | SCDR9 | HSDI7β13
Nonalcoholic fatty liver disease (NAFLD) is characterized by simple hepatic steatosis (SS), nonalcoholic steatohepatitis (NASH), hepatic fibrosis, and cirrhosis. Dysregulated fatty acid metabolism in the liver plays a critical role in the pathogenesis of NAFLD. Cytochrome P450 omega-hydroxylase 4A14 (CYP4A14) is a homolog of human CYP4A hydroxylase that catalyzes omega-hydroxylation of medium-chain fatty acids and arachidonic acid in mice. The goal of this study was to determine the role of CYP4A14 in the development and the progression of NAFLD. Here, we showed that hepatic CYP4A expression was up-regulated in the livers of patients and three murine models of NAFLD. Adenovirus-mediated overexpression of CYP4A14 in the livers of C57BL/6 mice resulted in a fatty liver phenotype with a significant increase in hepatic fatty acid translocase (FAT/CD36) expression. In contrast, CYP4A14 gene-deficient mice fed a high-fat diet or a methionine and choline-deficient (MCD) diet exhibited attenuated liver lipid accumulation and reduced hepatic FAT/CD36 expression. In addition, hepatic inflammation and fibrosis was markedly ameliorated in MCD diet-fed CYP4A14-deficient mice. Collectively, CYP4A14 plays an important role in the pathogenesis of both SS and NASH and may represent a potential therapeutic target for the treatment of NAFLD.
Prostaglandin E2 (PGE2) plays an important role in vascular homeostasis. Its receptor, E-prostanoid receptor 4 (EP4) is essential for physiological remodeling of the ductus arteriosus (DA). However, the role of EP4 in pathological vascular remodeling remains largely unknown. We found that chronic angiotensin II (AngII) infusion of mice with vascular smooth muscle cell (VSMC)-specific EP4 gene knockout (VSMC-EP4−/−) frequently developed aortic dissection (AD) with severe elastic fiber degradation and VSMC dedifferentiation. AngII-infused VSMC-EP4−/−mice also displayed more profound vascular inflammation with increased monocyte chemoattractant protein-1 (MCP-1) expression, macrophage infiltration, matrix metalloproteinase-2 and -9 (MMP2/9) levels, NADPH oxidase 1 (NOX1) activity, and reactive oxygen species production. In addition, VSMC-EP4−/−mice exhibited higher blood pressure under basal and AngII-infused conditions. Ex vivo and in vitro studies further revealed that VSMC-specific EP4 gene deficiency significantly increased AngII-elicited vasoconstriction of the mesenteric artery, likely by stimulating intracellular calcium release in VSMCs. Furthermore, EP4 gene ablation and EP4 blockade in cultured VSMCs were associated with a significant increase in MCP-1 and NOX1 expression and a marked reduction in α-SM actin (α-SMA), SM22α, and SM differentiation marker genes myosin heavy chain (SMMHC) levels and serum response factor (SRF) transcriptional activity. To summarize, the present study demonstrates that VSMC EP4 is critical for vascular homeostasis, and its dysfunction exacerbates AngII-induced pathological vascular remodeling. EP4 may therefore represent a potential therapeutic target for the treatment of AD.
The kidney is the central organ involved in maintaining water and sodium balance. In human kidneys, nine aquaporins (AQPs), including AQP1–8 and AQP11, have been found and are differentially expressed along the renal tubules and collecting ducts with distinct and critical roles in the regulation of body water homeostasis and urine concentration. Dysfunction and dysregulation of these AQPs result in various water balance disorders. This review summarizes current understanding of physiological and pathophysiological roles of AQPs in the kidney, with a focus on recent progress on AQP2 regulation by the nuclear receptor transcriptional factors. This review also provides an overview of AQPs as clinical biomarkers and therapeutic targets for renal diseases.
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