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Small Heterodimer Partner (small + heterodimer_partner)
Selected AbstractsFenofibrate differentially regulates plasminogen activator inhibitor-1 gene expression via adenosine monophosphate,activated protein kinase,dependent induction of orphan nuclear receptor small heterodimer partner,HEPATOLOGY, Issue 3 2009Dipanjan Chanda Plasminogen activator inhibitor type I (PAI-1) is a marker of the fibrinolytic system and serves as a possible predictor for hepatic metabolic syndromes. Fenofibrate, a peroxisome proliferator-activated receptor , (PPAR,) agonist, is a drug used for treatment of hyperlipidemia. Orphan nuclear receptor small heterodimer partner (SHP) plays a key role in transcriptional repression of crucial genes involved in various metabolic pathways. In this study, we show that fenofibrate increased SHP gene expression in cultured liver cells and in the normal and diabetic mouse liver by activating the adenosine monophosphate,activated protein kinase (AMPK) signaling pathway in a PPAR,-independent manner. Administration of transforming growth factor beta (TGF-,) or a methionine-deficient and choline-deficient (MCD) diet to induce the progressive fibrosing steatohepatitis model in C57BL/6 mice was significantly reversed by fenofibrate via AMPK-mediated induction of SHP gene expression with a dramatic decrease in PAI-1 messenger RNA (mRNA) and protein expression along with other fibrotic marker genes. No reversal was observed in SHP null mice treated with fenofibrate. Treatment with another PPAR, agonist, WY14643, showed contrasting effects on these marker gene expressions in wild-type and SHP null mice, demonstrating the specificity of fenofibrate in activating AMPK signaling. Fenofibrate exhibited a differential inhibitory pattern on PAI-1 gene expression depending on the transcription factors inhibited by SHP. Conclusion: By demonstrating that a PPAR,-independent fenofibrate-AMPK-SHP regulatory cascade can play a key role in PAI-1 gene down-regulation and reversal of fibrosis, our study suggests that various AMPK activators regulating SHP might provide a novel pharmacologic option in ameliorating hepatic metabolic syndromes. (HEPATOLOGY 2009.) [source] Molecular characterization of the role of orphan receptor small heterodimer partner in development of fatty liver,HEPATOLOGY, Issue 1 2007Jiansheng Huang The orphan receptor Small Heterodimer Partner (SHP, NROB2) regulates metabolic pathways, including hepatic bile acid, lipid, and glucose homeostasis. We reported that SHP- deletion in leptin-deficient OB,/, mice increases insulin sensitivity, and prevents the development of fatty liver. The prevention of steatosis in OB,/,/SHP,/, double mutants is not due to decreased body weight but is associated with increased hepatic very-low-density lipoprotein (VLDL) secretion and elevated microsomal triglyceride transfer protein (MTP) mRNA and protein levels. SHP represses the transactivation of the MTP promoter and the induction of MTP mRNA by LRH-1 in hepatocytes. Adenoviral overexpression of SHP inhibits MTP activity as well as VLDL-apoB protein secretion, and RNAi knockdown of SHP exhibits opposite effects. The expression of SHP in induced in fatty livers of OB,/, mice and other genetic or dietary models of steatosis, and acute overexpression of SHP by adenovirus, result in rapid accumulation of neutral lipids in hepatocytes. In addition, the pathways for hepatic lipid uptake and lipogenic program are also downregulated in OB,/,/SHP,/, mice, which may contribute to the decreased hepatic lipid content. Conclusion: These studies demonstrate that SHP regulates the development of fatty liver by modulating hepatic lipid export, uptake, and synthesis, and that the improved peripheral insulin sensitivity in OB,/,/SHP,/, mice is associated with decreased hepatic steatosis. (HEPATOLOGY 2007.) [source] ,Klotho: A new kid on the bile acid biosynthesis block,HEPATOLOGY, Issue 1 2006Marco Arrese We have generated a line of mutant mouse that lacks ,Klotho, a protein that structurally resembles Klotho. The synthesis and excretion of bile acids were found to be dramatically elevated in these mutants, and the expression of 2 key bile acid synthase genes, cholesterol 7,-hydroxylase (Cyp7a1) and sterol 12,- hydroxylase (Cyp8b1), was strongly upregulated. Nuclear receptor pathways and the enterohepatic circulation, which regulates bile acid synthesis, seemed to be largely intact; however, bile acid,dependent induction of the small heterodimer partner (SHP) NR0B2, a common negative regulator of Cyp7a1 and Cyp8b1, was significantly attenuated. The expression of Cyp7a1 and Cyp8b1 is known to be repressed by dietary bile acids via both SHP-dependent and -independent regulations. Interestingly, the suppression of Cyp7a1 expression by dietary bile acids was impaired, whereas that of Cyp8b1 expression was not substantially altered in ,klotho,/, mice. Therefore, ,Klotho may stand as a novel contributor to Cyp7a1 -selective regulation. Additionally, ,Klotho-knockout mice exhibit resistance to gallstone formation, which suggests the potential future clinical relevance of the ,Klotho system. [source] Combined loss of orphan receptors PXR and CAR heightens sensitivity to toxic bile acids in mice,HEPATOLOGY, Issue 1 2005Hirdesh Uppal Efficient detoxification of bile acids is necessary to avoid pathological conditions such as cholestatic liver damage and colon cancer. The orphan nuclear receptors PXR and CAR have been proposed to play an important role in the detoxification of xeno- and endo-biotics by regulating the expression of detoxifying enzymes and transporters. In this report, we showed that the combined loss of PXR and CAR resulted in a significantly heightened sensitivity to bile acid toxicity in a sex-sensitive manner. A regimen of lithocholic acid treatment, which was tolerated by wild-type and PXR null mice, caused a marked accumulation of serum bile acids and histological liver damage as well as an increased hepatic lipid deposition in double knockout males. The increased sensitivity in males was associated with genotype-specific suppression of bile acid transporters and loss of bile acid,mediated downregulation of small heterodimer partner, whereas the transporter suppression was modest or absent in females. The double knockout mice also exhibited gene- and tissue-specific dysregulation of PXR and CAR target genes in response to PXR and CAR agonists. In conclusion, although the cross-regulation of target genes by PXR and CAR has been proposed, the current study represents in vivo evidence of the combined loss of both receptors causing a unique pattern of gene regulation that can be translated into physiological events such as sensitivity to toxic bile acids. (HEPATOLOGY 2005;41:168,176.) [source] Analysis of bile acid-induced regulation of FXR target genes in human liver slicesLIVER INTERNATIONAL, Issue 1 2007Diana Jung Abstract Information about the role of nuclear receptors has rapidly increased over the last decade. However, details about their role in human are lacking. Owing to species differences, a powerful human in vitro system is needed. This study uses for the first time precision-cut human liver slices in the nuclear receptor field. The farnesoid X receptor (FXR) was chosen as a model. We were able to demonstrate that human liver slices efficiently take up bile acids and show a stable expression of a wide variety of genes relevant for bile acid metabolism, including bile acid transporters, cytochrome P450 enzymes and transcription factors. Treatment with chenodeoxycholate induced small heterodimer partner, bile salt export pump and p-glycoprotein, ABCB4 and repressed cholesterol 7, hydroxylase, hepatocyte nuclear factor (HNF)1, HNF4 and organic anion transporting peptide (OATP)1B1. OATP1B3, FXR, HNF3, and cytochrome P450 enzyme remained relatively constant. In contrast to what has been observed in mice and rat studies, SHP induction did not result in repression of sodium-dependent bile acid cotransporter expression. Further, regulation of genes seemed to be dependent on concentration and time. Taken together, the study shows that the use of liver slices is a powerful technique that enables to study nuclear receptors in the human liver. [source] Dietary procyanidins lower triglyceride levels signaling through the nuclear receptor small heterodimer partnerMOLECULAR NUTRITION & FOOD RESEARCH (FORMERLY NAHRUNG/FOOD), Issue 10 2008Josep Maria Del Bas Abstract Hypertriglyceridemia is an independent risk factor in the development of cardiovascular diseases, and we have previously reported that oral administration of a grape seed procyanidin extract (GSPE) drastically decreases plasma levels of triglycerides (TG) and apolipoprotein B (ApoB) in normolipidemic rats, with a concomitant induction in the hepatic expression of the nuclear receptor small heterodimer partner (NR0B2/SHP). Our objective in this study was to elucidate whether SHP is the mediator of the reduction of TG-rich ApoB-containing lipoproteins triggered by GSPE. We show that GSPE inhibited TG and ApoB secretion in human hepatocarcinoma HepG2 cells and had and hypotriglyceridemic effect in wild-type mouse. The TG-lowering action of GSPE was abolished in HepG2 cells transfected with a SHP-specific siRNA and in a SHP-null mouse. Moreover, in mouse liver, GSPE downregulated several lipogenic genes, including steroid response element binding protein 1c (SREBP-1c), and upregulated carnitine palmitoyltransferase-1A (CPT-1A) and apolipoprotein A5 (ApoA5), in a SHP-dependent manner. In HepG2 cells GSPE also inhibited ApoB secretion, but in a SHP-independent manner. In conclusion, SHP is a key mediator of the hypotriglyceridemic response triggered by GSPE. This novel signaling pathway of procyanidins through SHP may be relevant to explain the health effects ascribed to the regular consumption of dietary flavonoids. [source] | ||||||||||