Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002895 (sickle cell disease)
 11,747 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leptin elicits a metabolic response that cannot be explained by its anorectic effects alone. To examine the mechanism underlying leptin's metabolic actions, we used transcription profiling to identify leptin-regulated genes in ob/ob liver. Leptin was found to specifically repress RNA levels and enzymatic activity of hepatic stearoyl-CoA desaturase-1 (SCD-1), which catalyzes the biosynthesis of monounsaturated fatty acids. Mice lacking SCD-1 were lean and hypermetabolic. ob/ob mice with mutations in SCD-1 were significantly less obese than ob/ob controls and had markedly increased energy expenditure. ob/ob mice with mutations in SCD-1 had histologically normal livers with significantly reduced triglyceride storage and VLDL (very low density lipoprotein) production. These findings suggest that down-regulation of SCD-1 is an important component of leptin's metabolic actions.
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PMID:Role for stearoyl-CoA desaturase-1 in leptin-mediated weight loss. 1553 82

The importance of insulin for the in vivo effects of growth hormone (GH) on lipid and lipoprotein metabolism was investigated by examining the effects of GH treatment of hypophysectomized (Hx) female rats with and without concomitant insulin treatment. Hypophysectomy-induced changes of HDL, apolipoprotein (apo)E, LDL, and apoB levels were normalized by GH treatment but not affected by insulin treatment. The hepatic triglyceride secretion rate was lower in Hx rats than in normal rats and increased by GH treatment. This effect of GH was blunted by insulin treatment. The triglyceride content in the liver changed in parallel with the changes in triglyceride secretion rate, indicating that the effect of the hormones on triglyceride secretion was dependent on changed availability of triglycerides for VLDL assembly. GH and insulin independently increased editing of apoB mRNA, but the effects were not additive. The expression of fatty-acid synthase (FAS), stearoyl-CoA desaturase-1 (SCD-1), and sterol regulatory element-binding protein-1c (SREBP-1c) was increased by GH treatment. Insulin and GH had no additive effects on these genes; instead, insulin blunted the effect of GH on SREBP-1c mRNA. In contrast to the liver, adipose tissue expression of SREBP-1c, FAS, or SCD-1 mRNA was not influenced by GH. In conclusion, the increased hepatic expression of lipogenic enzymes after GH treatment may be explained by increased expression of SREBP-1c. Insulin does not mediate the effects of GH but inhibits the stimulatory effect of GH on hepatic SREBP-1c expression and triglyceride secretion rate.
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PMID:Interaction between growth hormone and insulin in the regulation of lipoprotein metabolism in the rat. 1237 31

Strategies to stimulate endogenous surfactant production require a detailed understanding of the regulation of lipogenesis in alveolar type II cells. We developed culture conditions in which keratinocyte growth factor (KGF) stimulates fatty acid and phospholipid synthesis. KGF stimulated acetate incorporation into phosphatidylcholine, disaturated phosphatidylcholine, and phosphatidylglycerol more than 5% rat serum alone. To determine the mRNA levels of lipogenic enzymes and transport proteins, we analyzed gene expression by oligonucleotide microarrays. KGF increased the mRNA levels for fatty acid synthase, stearoyl-CoA desaturase-1 (SCD-1), and epidermal fatty acid-binding protein more than rat serum alone. In addition, KGF increased the mRNA levels of the transcription factors CCAAT/enhancer-binding protein alpha (C/EBPalpha) and C/EBPdelta as well as SREBP-1c (ADD-1), but not PPARgamma. These changes in C/EBPalpha and C/EBPdelta were confirmed by in situ hybridization. SCD-1 was also found to be highly expressed in alveolar type II cells in vivo. Furthermore, KGF increased protein levels of fatty acid synthase, C/EBPalpha, C/EBPdelta, SREBP-1, epidermal fatty acid-binding protein, and SCD. Finally, the liver X receptor agonist T0901317 increased acetate incorporation and SREBP-1 but not SREBP-2 protein levels. In summary, KGF stimulates lipogenesis in type II cells by a coordinated expression of lipogenic enzymes and transport proteins regulated by C/EBP isoforms and SREBP-1c.
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PMID:Keratinocyte growth factor and the transcription factors C/EBP alpha, C/EBP delta, and SREBP-1c regulate fatty acid synthesis in alveolar type II cells. 1286 12

Alveolar type II cells increase lipogenesis and convert glycogen into the phospholipids of surfactant in the late term fetal lung. Recent studies suggest that CCAAT/enhancing-binding protein (C/EBP) isoforms and sterol regulatory element binding protein (SREBP)-1c regulate fatty acid synthesis in adult type II cells in vitro. To define the temporal relationships and enzymes involved in lipogenesis in fetal rat lung, the mRNA levels of selected transcription factors and enzymes were determined. There was an increase in the mRNA levels of C/EBPalpha, C/EBPbeta, C/EBPdelta, peroxisomal proliferator-activated receptor gamma (PPARgamma), and SREBP-1c, but not SREBP-1a or SREBP-2 from fetal Days 19-21. There was also an increase in the mRNA levels of fatty acid synthase, stearoyl-CoA desaturase 1 (SCD-1), fatty acid translocase, glycerol-3-P acyl transferase, and phosphatidate cytidylyltransferase. By in situ hybridization, there was detectible expression of fatty acid synthase, SCD-1, and C/EBPalpha along the alveolar septae with the same distribution pattern as surfactant protein-C, whereas PPARgamma expression appeared to be restricted to macrophages. Regulation of lipogenesis at the mRNA level is predominately on enzymes of fatty acid synthesis and appears to be regulated by C/EBPalpha and SREBP-1c. SCD-1 and phosphatidate cytidylyltransferase are important components of the lipogenic response in the fetal lung that have not been recognized previously.
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PMID:Lipogenesis in fetal rat lung: importance of C/EBPalpha, SREBP-1c, and stearoyl-CoA desaturase. 1289 75

Adipocyte differentiation of mouse embryonic fibroblasts (MEFs) derived from c-Src wild-type or c-Src-deficient (abbreviated as MEF+/+ and MEF-/- hereafter) C57BL/6 mice was induced by ascorbic acid (A) and beta-glycerophosphate (G). TCDD clearly suppressed differentiation of MEF+/+, but not MEF-/-, as measured by increased accumulation of triglycerides associated with increased expression of adipocyte differentiation-specific genes such as peroxisome proliferators activated receptor (PPAR)gamma, stearoyl-CoA desaturase (SCD-1). Studies on inducibility of TCDD-activated genes such as cytochrome P450 (CYP)1A1 and CYP1B1 revealed a comparable dose response in both MEF+/+ and MEF-/-. Furthermore, the binding activity of AhR complexes to xenobiotic response elements (XREs) was similar in both cell lines. We further studied the effect of TCDD on CCAAT/enhancer binding proteins (C/EBP), which are known to be important regulators of cell differentiation. TCDD induced C/EBPbeta and C/EBPdelta mRNA expression and DNA binding activity in a time- and dose-dependent manner in MEF+/+ but not in MEF-/-. The levels of C/EBPbeta and C/EBPdelta were still elevated in differentiated MEF+/+ after 10 days of treatment with TCDD. In MEF-/-, C/EBPbeta and C/EBPdelta are highly expressed constitutively. In contrast to MEF+/+, TCDD does not cause any significant change of these transcription factors in MEF-/-. These data indicate that suppression of differentiation by TCDD in MEF requires a functional c-Src activity and induced levels of C/EBPbeta and C/EBPdelta, including their maintenance at high levels by TCDD, rather than ultimate high levels of these C/EBP isoforms.
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PMID:Interaction of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) with induced adipocyte differentiation in mouse embryonic fibroblasts (MEFs) involves tyrosine kinase c-Src. 1450 2

A sucrose-rich diet, as compared with a similar starch diet, induces a time-dependent typical noninsulin-dependent diabetes syndrome characterized by insulin resistance in rats. Within the first 3 wk, there was glucose intolerance associated with hyperinsulinemia, hypertriglyceridemia, and high plasma FFA. In this study, we examined the effect of the sucrose-rich diet vs. the starch diet during short- (3 wk) and longterm treatment (6 mon) on hepatic delta9, delta6, and delta5 desaturases. These enzymes modulate monounsaturated FA and PUFA biosynthesis, respectively. Sucrose feeding (3 wk) caused an initial hyperinsulinemia that was normalized within 6 mon. In the early period (3 wk), stearoyl-CoA desaturase-1 (SCD-1) mRNA and activity were decreased, whereas delta6 desaturase mRNA abundance and delta6 and delta5 desaturase activities remained unchanged. After 6 mon of sucrose feeding, activities of the delta9, delta6, and delta5 desaturases were each increased. The SCD-1 and delta6 desaturase mRNA were also correspondingly higher. These increases were consistent with an increase in oleic acid, the 20:4/18:2 ratio, and 22:4n-6 and 22:5n-6 acids in liver and muscle lipids. On the other hand, the percentage of 22:6n-3 acid was decreased. In conclusion, a sucrose-rich diet after 6 mon induces an increase in rat liver SCD-1 and delta6 desaturase mRNA and enzymatic activities that are opposite to the changes reported in insulin-dependent diabetes mellitus. It appears that neither blood insulin levels nor insulin resistance is a factor affecting the delta9, delta6, and delta5 desaturase changes in mRNA and activity found with the sucrose-rich diet.
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PMID:Desaturase activities in rat model of insulin resistance induced by a sucrose-rich diet. 1450 36

The incidence of obesity has increased dramatically in recent years, making it one of the most pressing public health concerns worldwide. Obesity is commonly associated with comorbid conditions, most notably diabetes, coronary artery disease, and hypertension, and the coexistence of these diseases has been termed the Metabolic Syndrome. The identification of the hormone leptin provided a molecular link to obesity. Leptin is recognized as the central mediator in an endocrine circuit regulating energy homeostasis. Leptin administration leads to hypophagia, increased energy expenditure, and weight loss, while leptin deficiency enacts an adaptive response to starvation manifested by hyperphagia, decreased energy expenditure, and suppression of the neuroendocrine axis. While elucidation of leptin's role has permitted a more detailed view of the biology underlying energy homeostasis, most obese individuals are leptin resistant. A more complete understanding of the molecular components of the leptin pathway is necessary to develop effective treatment for obesity and the Metabolic Syndrome. The identification and role of one such component, stearoyl-CoA desaturase-1 (SCD-1), is reviewed here. Leptin's actions are not due to its anorectic effects alone. Leptin also mediates specific metabolic effects, including the potent depletion of triglyceride from liver and other peripheral tissues. To explore the molecular basis by which leptin depletes hepatic lipid, we used oligonucleotide arrays to identify genes in liver whose expression was modulated by leptin treatment. An algorithm was created that identified and ranked genes specifically repressed by leptin. The gene ranking at the top of this list was SCD-1, the rate limiting enzyme in the biosynthesis of monounsaturated fats. SCD-1 was specifically repressed during leptin-mediated weight loss, and mice lacking SCD-1 showed markedly reduced adiposity on both a lean and ob/ob background (ab(J)/ab(J); ob/ob), despite higher food intake. ab(J)/ab(J); ob/ob mice also showed a complete correction of the hypometabolic phenotype and hepatic steatosis of ob/ob mice, suggesting that fatty acid oxidation is enhanced in the absence of SCD-1. These findings indicate that pharmacologic manipulation of SCD-1 may be of benefit in the treatment of obesity, diabetes, hepatic steatosis, and other components of the Metabolic Syndrome.
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PMID:Stearoyl-CoA desaturase-1 and the metabolic syndrome. 1468 58

Lipodystrophy is characterized by the complete or partial absence of adipose tissue, insulin resistance, hepatic steatosis, and leptin deficiency. Here, we show that low-dose central leptin corrects the insulin resistance and fatty liver of lipodystrophic aP2-nSREBP-1c mice, while the same dose given peripherally does not. Central leptin also repressed stearoyl-CoA desaturase-1 (SCD-1) RNA and enzymatic activity, which were increased in livers of lipodystrophic mice. aP2-nSREBP-1c mice homozygous for an SCD-1 deletion had markedly reduced hepatic steatosis, increased saturated fatty acids, decreased acetyl-CoA carboxylase activity, and decreased malonyl-CoA levels in the liver. Despite the reduction in hepatic steatosis, these mice remained diabetic. A leptin dose-response curve showed that subcutaneous leptin improved hyperglycemia and hyperinsulinemia in aP2-nSREBP-1c mice at doses that did not substantially alter hepatic steatosis or hepatic SCD enzymatic activity. Leptin treatment at this dose improved insulin-stimulated insulin receptor and insulin receptor substrate 2 (IRS-2) phosphorylation, IRS-2-associated PI3K activity, and Akt activity in liver. Together, these data suggest that CNS-mediated repression of SCD-1 contributes to leptin's antisteatotic actions. Intracerebroventricular leptin improves glucose homeostasis by improving insulin signal transduction in liver, but in this case the effect appears to be independent of SCD-1.
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PMID:Site and mechanism of leptin action in a rodent form of congenital lipodystrophy. 1475 38

Herein, we exploit the power of global lipidomics to identify the critical role of peroxisomal processing of fatty acids in adipocyte lipid storage and metabolism. Remarkably, 3T3-L1 differentiating adipocytes rapidly acquired the ability to alpha oxidize unbranched fatty acids, which is manifested in the accumulation of odd chain length unbranched fatty acids in all major lipid classes. Moreover, in differentiating adipocytes, unsaturated odd chain length fatty acids in TAG molecular species contained exclusively Delta9 olefinic linkages. Unsaturated fatty acids (e.g., oleic and palmitoleic acids) were not subject to alpha oxidation, resulting in the absence of Delta8 unsaturated odd chain length fatty acids. This highly selective substrate utilization resulted in the obligatory sequential ordering of alpha oxidation prior to Delta9 desaturation. On the basis of these results, a putative type 2 peroxisomal localization sequence was identified at the N-terminus of mouse stearoyl-CoA desaturase I (SCD I) comprised of (30)KVKTVPLHL(38). Kinetic analysis demonstrated that the rate of alpha oxidation of exogenously administered [9,10-(3)H]palmitic acid increased 4-fold during differentiation. Similarly, quantitative PCR demonstrated a 4-fold increase in phytanoyl-CoA alpha hydroxylase (PAHX) and fatty acyl-CoA oxidase (FACO) mRNA levels during differentiation. Collectively, these results underscore the role of peroxisomal fatty acid processing as an important determinant of the metabolic fate of fatty acids in the differentiating adipocyte.
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PMID:Sequential ordered fatty acid alpha oxidation and Delta9 desaturation are major determinants of lipid storage and utilization in differentiating adipocytes. 1510 62

We investigated whether the sexually dimorphic secretory pattern of growth hormone (GH) in the rat regulates hepatic gene expression of sterol regulatory element-binding protein-1c (SREBP-1c) and its target genes. SREBP-1c, fatty acid synthase (FAS), and glycerol-3-phosphate acyltransferase (GPAT) mRNA were more abundant in female than in male livers, whereas acetyl-CoA carboxylase-1 (ACC1) and stearoyl-CoA desaturase-1 (SCD-1) were similarly expressed in both sexes. Hypophysectomized female rats were given GH as a continuous infusion or as two daily injections for 7 days to mimic the female- and male-specific GH secretory patterns, respectively. The female pattern of GH administration increased the expression of SREBP-1c, ACC1, FAS, SCD-1, and GPAT mRNA, whereas the male pattern of GH administration increased only SCD-1 mRNA. FAS and SCD-1 protein levels were regulated in a similar manner by GH. Incubation of primary rat hepatocytes with GH increased SCD-1 mRNA levels and decreased FAS and GPAT mRNA levels but had no effect on SREBP-1c mRNA. GH decreased hepatic liver X receptor-alpha (LXRalpha) mRNA levels both in vivo and in vitro. Feminization of the GH plasma pattern in male rats by administration of GH as a continuous infusion decreased insulin sensitivity and increased expression of FAS and GPAT mRNA but had no effect on SREBP-1c, ACC1, SCD-1, or LXRalpha mRNA. In conclusion, FAS and GPAT are specifically upregulated by the female secretory pattern of GH. This regulation is not a direct effect of GH on hepatocytes and does not involve changed expression of SREBP-1c or LXRalpha mRNA but is associated with decreased insulin sensitivity.
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PMID:Effects of gender and GH secretory pattern on sterol regulatory element-binding protein-1c and its target genes in rat liver. 1528 Jan 51


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