Significance: Nonalcoholic fatty liver disease (NAFLD) is a common chronic hepatic disease affecting up to 25% of subjects in the developed world, and represents a progressive illness eventually leading to liver fibrosis and cirrhosis. This study reports an extensive set of human liver lipid droplet (LD)-associated proteins and an array of proteins differentially expressed in human NAFLD. We also uncover 17β-hydroxysteroid dehydrogenase-13, a newly identified LD-associated protein, as a pathogenic molecule in the development of NAFLD. The present study provides a potential link between LD proteins and the pathogenesis of hepatic steatosis.

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.

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.

Significance: AD is a lethal vascular disease with a high mortality. The present study reports a critical role of prostaglandin E2 receptor EP4 in the pathogenesis of AD. VSMC-specific EP4 deletion (VSMC-EP4 ^−/− ) significantly increases the incidence and severity of AngII-induced aortic aneurysm and dissection. Compared with WT mice, VSMC-EP4 ^−/− mice exhibit increased vascular inflammation, oxidative stress, elastic fiber degradation, and VSMC dedifferentiation following chronic AngII infusion. VSMC-EP4 ^−/− mice also have higher blood pressure under basal and AngII-infused conditions. Our findings demonstrate that VSMC-EP4 plays an important role in the maintenance of vascular integrity and blood pressure and may represent a potential therapeutic target for the treatment of AD as well as hypertension.

The farnesoid X receptor (FXR) is a ligand-activated transcription factor belonging to the nuclear receptor superfamily. FXR is mainly expressed in liver and small intestine, where it plays an important role in bile acid, lipid, and glucose metabolism. The kidney also has a high FXR expression level, with its physiological function unknown. Here we demonstrate that FXR is ubiquitously distributed in renal tubules. FXR agonist treatment significantly lowered urine volume and increased urine osmolality, whereas FXR knockout mice exhibited an impaired urine concentrating ability, which led to a polyuria phenotype. We further found that treatment of C57BL/6 mice with chenodeoxycholic acid, an FXR endogenous ligand, significantly up-regulated renal aquaporin 2 (AQP2) expression, whereas FXR gene deficiency markedly reduced AQP2 expression levels in the kidney. In vitro studies showed that the AQP2 gene promoter contained a putative FXR response element site, which can be bound and activated by FXR, resulting in a significant increase of AQP2 transcription in cultured primary inner medullary collecting duct cells. In conclusion, the present study demonstrates that FXR plays a critical role in the regulation of urine volume, and its activation increases urinary concentrating capacity mainly via up-regulating its target gene AQP2 expression in the collecting ducts. Significance Farnesoid X (FXR) receptor is a ligand-activated transcription factor that regulates bile acid, lipid and glucose metabolism. It can be activated by endogenous bile acids, including chenodeoxycholic acid. This study uncovers a unique role for FXR to regulate urine volume independently of antidiuretic hormone and identifies aquaporin 2 as a direct target gene of FXR in renal collecting ducts. These findings provide a unique mechanism involved in the regulation of urinary concentrating process. The present study may also help understand the pathogenesis of hepatorenal syndrome, a state with increased circulating bile acid levels and impaired renal function.