Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0015695 (fatty liver)
13,941 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cyclin D1 gene is overexpressed in human breast cancers and is required for oncogene-induced tumorigenesis. Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor selectively activated by ligands of the thiazolidinedione class. PPAR gamma induces hepatic steatosis, and liganded PPAR gamma promotes adipocyte differentiation. Herein, cyclin D1 inhibited ligand-induced PPAR gamma function, transactivation, expression, and promoter activity. PPAR gamma transactivation induced by the ligand BRL49653 was inhibited by cyclin D1 through a pRB- and cdk-independent mechanism, requiring a region predicted to form an helix-loop-helix (HLH) structure. The cyclin D1 HLH region was also required for repression of the PPAR gamma ligand-binding domain linked to a heterologous DNA binding domain. Adipocyte differentiation by PPAR gamma-specific ligands (BRL49653, troglitazone) was enhanced in cyclin D1(-/-) fibroblasts and reversed by retroviral expression of cyclin D1. Homozygous deletion of the cyclin D1 gene, enhanced expression by PPAR gamma ligands of PPAR gamma and PPAR gamma-responsive genes, and cyclin D1(-/-) mice exhibit hepatic steatosis. Finally, reduction of cyclin D1 abundance in vivo using ponasterone-inducible cyclin D1 antisense transgenic mice, increased expression of PPAR gamma in vivo. The inhibition of PPAR gamma function by cyclin D1 is a new mechanism of signal transduction cross talk between PPAR gamma ligands and mitogenic signals that induce cyclin D1.
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PMID:Cyclin D1 repression of peroxisome proliferator-activated receptor gamma expression and transactivation. 1291 38

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor, which controls adipocyte differentiation. We targeted with homologous recombination the PPAR gamma 2-specific exon B, resulting in a white adipose tissue knockdown of PPAR gamma. Although homozygous (PPAR gamma hyp/hyp) mice are born with similar weight as the WT mice, the PPAR gamma hyp/hyp animals become growth retarded and develop severe lipodystrophy and hyperlipidemia. Almost half of these PPAR gamma hyp/hyp mice die before adulthood, whereas the surviving PPAR gamma hyp/hyp animals overcome the growth retardation, yet remain lipodystrophic. In contrast to most lipodystrophic models, the adult PPAR gamma hyp/hyp mice only have mild glucose intolerance and do not have a fatty liver. These metabolic consequences of the lipodystrophy are relatively benign because of the induction of a compensatory gene expression program in the muscle that enables efficient oxidation of excess lipids. The PPAR gamma hyp/hyp mice unequivocally demonstrate that PPAR gamma is the master regulator of adipogenesis in vivo and establish that lipid and glucose homeostasis can be relatively well maintained in the absence of white adipose tissue.
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PMID:Compensation by the muscle limits the metabolic consequences of lipodystrophy in PPAR gamma hypomorphic mice. 1460 33

Fasting triggers a series of hormonal cues that promote energy balance by inducing glucose output and lipid breakdown in the liver. In response to pancreatic glucagon and adrenal cortisol, the cAMP-responsive transcription factor CREB activates gluconeogenic and fatty acid oxidation programmes by stimulating expression of the nuclear hormone receptor coactivator PGC-1 (refs 2-5). In parallel, fasting also suppresses lipid storage and synthesis (lipogenic) pathways, but the underlying mechanism is unknown. Here we show that mice deficient in CREB activity have a fatty liver phenotype and display elevated expression of the nuclear hormone receptor PPAR-gamma, a key regulator of lipogenic genes. CREB inhibits hepatic PPAR-gamma expression in the fasted state by stimulating the expression of the Hairy Enhancer of Split (HES-1) gene, a transcriptional repressor that is shown here to be a mediator of fasting lipid metabolism in vivo. The coordinate induction of PGC-1 and repression of PPAR-gamma by CREB during fasting provides a molecular rationale for the antagonism between insulin and counter-regulatory hormones, and indicates a potential role for CREB antagonists as therapeutic agents in enhancing insulin sensitivity in the liver.
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PMID:CREB controls hepatic lipid metabolism through nuclear hormone receptor PPAR-gamma. 1461 8

Non-alcoholic steatohepatitis (NASH) may progress to liver cirrhosis, and NASH patients with liver cirrhosis have a risk of development of hepatocellular carcinoma. Peroxisome proliferator-activated receptor (PPAR) gamma ligand has recently been reported to have improved the condition of patients with NASH. The aim of this study was to investigate whether pioglitazone, a PPARgamma ligand, has any influence on the animal model of NASH as well as isolated hepatic stellate cells. In vivo, the effects of pioglitazone were examined using the choline-deficient L-amino acid-defined (CDAA)-diet liver fibrosis model. After two weeks, pioglitazone improved hepatic steatosis, prevented liver fibrosis, and reduced preneoplastic lesions in the liver after 10 weeks. Pioglitazone reduced the expression of TIMP-1 and TIMP-2 mRNA without changing MMP-13 mRNA expression compared to the liver fed a CDAA diet alone. In vitro, pioglitazone prevented the activation of hepatic stellate cells resulting in reducing the expression of type I procollagen, MMP-2, TIMP-1, and TIMP-2 mRNA with increased MMP-13 mRNA expression. These results indicate that pioglitazone may be one of the candidates for the benefit drugs for the liver disease of patients with NASH.
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PMID:Pioglitazone prevents hepatic steatosis, fibrosis, and enzyme-altered lesions in rat liver cirrhosis induced by a choline-deficient L-amino acid-defined diet. 1501 44

We recently identified mutations in the lipin gene, Lpin1, as the cause of lipodystrophy in the fatty liver dystrophy (fld) mouse. Here we identify impaired adipocyte differentiation as the basis for lipodystrophy in lipin-deficient mice and demonstrate that lipin is required for normal induction of the adipogenic gene transcription program. We found that the reduced adiposity in chow fed fld mice and resistance to obesity in fld mice fed a high-fat diet is associated with reduced adipogenic gene expression. Using primary mouse embryonic fibroblasts isolated from fld mice, we confirmed that lipin deficiency prevents normal lipid accumulation and induction of key adipogenic genes, including peroxisome proliferator-activated receptor (PPAR)gamma and CCAAT enhancer-binding protein (C/EBP)alpha. However, our previous studies of daily gene expression in differentiating 3T3-L1 preadipocytes indicated that lipin expression is undetectable until about day 3 of differentiation, at a point after PPARgamma and C/EBPalpha gene expression is established. This paradox was resolved by examining gene expression at 10-h intervals during 3T3-L1 cell differentiation, leading to detection of transient lipin expression at 10 h into the differentiation program, prior to the induction of PPARgamma and C/EBPalpha. Consistent with a requirement for lipin expression upstream of PPARgamma, differentiation of lipin-deficient mouse embryonic fibroblasts could be rescued by ectopic expression of PPARgamma. Thus, we conclude that lipin expression is required prior to PPARgamma during adipocyte differentiation.
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PMID:Lipin expression preceding peroxisome proliferator-activated receptor-gamma is critical for adipogenesis in vivo and in vitro. 1512 8

NADPH is an essential cofactor for many enzymatic reactions including glutathione metabolism and fat and cholesterol biosynthesis. We have reported recently an important role for mitochondrial NADP(+)-dependent isocitrate dehydrogenase in cellular defense against oxidative damage by providing NADPH needed for the regeneration of reduced glutathione. However, the role of cytosolic NADP(+)-dependent isocitrate dehydrogenase (IDPc) is still unclear. We report here for the first time that IDPc plays a critical role in fat and cholesterol biosynthesis. During differentiation of 3T3-L1 adipocytes, both IDPc enzyme activity and its protein content were increased in parallel in a time-dependent manner. Increased expression of IDPc by stable transfection of IDPc cDNA positively correlated with adipogenesis of 3T3-L1 cells, whereas decreased IDPc expression by an antisense IDPc vector retarded adipogenesis. Furthermore, transgenic mice with overexpressed IDPc exhibited fatty liver, hyperlipidemia, and obesity. In the epididymal fat pads of the transgenic mice, the expressions of adipocyte-specific genes including peroxisome proliferator-activated receptor gamma were markedly elevated. The hepatic and epididymal fat pad contents of acetyl-CoA and malonyl-CoA in the transgenic mice were significantly lower, whereas the total triglyceride and cholesterol contents were markedly higher in the liver and serum of transgenic mice compared with those measured in wild type mice, suggesting that the consumption rate of those lipogenic precursors needed for fat biosynthesis must be increased by elevated IDPc activity. Taken together, our findings strongly indicate that IDPc would be a major NADPH producer required for fat and cholesterol synthesis.
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PMID:Cytosolic NADP+-dependent isocitrate dehydrogenase plays a key role in lipid metabolism. 1525 34

Adiposity positively correlates with insulin resistance and is a major risk factor of type 2 diabetes. Administration of exogenous insulin, which acts as an anabolic factor, facilitates adipogenesis. Recently nonpeptidal insulin receptor (IR) activators have been discovered. Here we evaluate the effects of the orally bioavailable small-molecule IR activator (Compound-2) on metabolic abnormalities associated with type 2 diabetes using a nongenetic mouse model in comparison with the effects of a novel non-thiazolidinedione (nTZD) peroxisome proliferator-activated receptor-gamma agonist. Both Compound-2 and nTZD alleviated fasting and postprandial hyperglycemia; accelerated glucose clearance rate; and normalized plasma levels of nonesterified fatty acids, triglycerides, and leptin. Unlike nTZD, which increased body weight gain, and total fat mass, which is a common feature for PPARgamma agonists, Compound-2 prevented body weight gain and hypertrophy of brown, and white adipose tissue depots and the development of hepatic steatosis in the mouse model of type 2 diabetes. The effect of the two compounds on proximal steps in insulin signal transduction pathway was analyzed in tissues. Compound-2 enhanced insulin-stimulated phosphorylation of IR tyrosine and/or Akt in the liver, skeletal muscle, and white adipose tissue, whereas nTZD potentiated the phosphorylation of IR and Akt in the adipose tissue only. In conclusion, small-molecule IR activators have unique features as insulin sensitizers and hold potential utility in the treatment of type 2 diabetes and obesity.
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PMID:Small-molecule insulin mimetic reduces hyperglycemia and obesity in a nongenetic mouse model of type 2 diabetes. 1529 48

Peroxisome proliferator-activated receptor (PPAR) isoforms, alpha, gamma and beta/delta, function as important lipid sensors as well as key regulators of energy homeostasis. PPARalpha plays a dynamic role in energy combustion by transcriptionally upregulating fatty acid oxidation systems primarily in liver, whereas PPARgamma functions as a regulator of adipogenesis and lipid storage. Overexpression of PPARgamma, using adenoviral expression approach, in PPARalpha deficient mouse liver results in hepatic steatosis with concurrent expression of adipocyte specific genes. In this study, to gain a global molecular understanding of PPARgamma1-induced gene expression in liver, we have analyzed gene expression profiles using the Affymetrix GeneChip mouse expression array set 430, that enables a comprehensive gene expression profiling with >39,000 transcripts. Microarray data analysis provided us with over 278 genes up-regulated fourfold or higher, and 121 genes down-regulated fourfold or higher in liver with PPARgamma-induced hepatic adiposis. We have found 101 uncharacterized genes out of 278 up-regulated and 29 uncharacterized among the down-regulated gene categories, respectively. Of 177 functionally characterized candidate genes in the up-regulated category many appear to be involved in adipogenesis, lipid metabolism and signal transduction. To focus attention on the uncharacterized genes in the up-regulated category, we cloned the full-length cDNAs of two novel candidates, which we designated as promethin and PGLP. Promethin, a 15-kDa cytosolic protein, is not normally expressed in liver but induced robustly in liver with hepatic adiposis caused by PPARgamma overexpression. PGLP, which encodes a 38 kDa cytoplasmic membranous protein, is a low abundant transcript in normal liver, but induced dramatically following PPARgamma overexpression. The expression of these two genes was not increased in fatty livers induced by fasting or choline deficiency. The identification of these and other novel PPARgamma-target genes should provide a basis for understanding the molecular mechanisms underlying energy storage and lipid homeostasis.
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PMID:Identification of promethin and PGLP as two novel up-regulated genes in PPARgamma1-induced adipogenic mouse liver. 1558 83

Pathogenic role of intrahepatic lipid accumulation in insulin resistance and metabolic syndrome has been well documented. Liver steatosis constitutes a risk factor for nonalcoholic steatohepatitis (NASH), one of the leading causes of obesity-related morbidity and mortality. Although pathophysiology of steatosis is multifactorial, a line of evidence from rodent studies suggests that PPARalpha and PPARgamma are involved. PPARalpha is highly expressed in liver and its activation by agonists leads to augmented fatty acid oxidation and protects against steatosis. PPARgamma, which is transcriptionally up-regulated in steatosis, activates lipogenic enzymes and exacerbates steatosis. However, recent human studies have suggested that PPARgamma agonists improve NASH possibly by its primary insulin-sensitizing effect on adipocytes. PPARs modulation is becoming a rational and effective therapeutic approach for the treatment of nonalcoholic fatty liver disease.
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PMID:[Role of PPARs in the pathophysiology of nonalcoholoic fatty liver disease]. 1582 40

Obesity is not necessary to observe insulin resistance in humans since severe insulin resistance also characterizes patients lacking subcutaneous fat such as those with HAART (highly-active antiretroviral therapy) - associated lipodystrophy. Both the obese and the lipodystrophic patients have, however, an increase in the amount of fat hidden in the liver. Liver fat content can be non-invasively accurately quantified by proton magnetic resonance spectroscopy. It is closely correlated with fasting insulin and direct measures of hepatic insulin sensitivity while the amount of subcutaneous adipose tissue is not. The causes of interindividual variation in liver fat content independent of obesity are largely unknown but could involve differences in signals from adipose tissue such as in the amount of adiponectin produced and differences in fat intake. Adiponectin deficiency characterizes both lipodystrophic and obese insulin resistant individuals, and serum levels correlate with liver fat content. Liver fat content can be decreased by weight loss. In addition, treatment of both lipodystrophic and type 2 diabetic patients with PPARgamma agonists but not metformin decreases liver fat and increases adiponectin levels. Markers of liver fat such as serum alanine aminotransferase activity have been shown to predict type 2 diabetes in several studies independent of obesity. The fatty liver thus may help to explain why some but not all obese individuals are insulin resistant and why even lean individuals may be insulin resistant, and thereby at risk of developing type 2 diabetes and cardiovascular disease.
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PMID:The fatty liver and insulin resistance. 1589 48


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