Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The definable causes of nonalcoholic steatohepatitis (NASH) include jejunoileal bypass surgery (JIB), other causes of rapid and profound weight loss in obese subjects, total parenteral nutrition, drugs, industrial toxins, copper toxicity, and disorders characterized by extreme insulin resistance. However, the etiopathogenesis in most cases of NASH appears multifactorial. Obesity, type 2 diabetes, and hypertriglyceridemia are often associated with hepatic steatosis, and although this does not invariably lead to NASH, the fatty liver is vulnerable to hepatocellular injury initiated by reactive oxygen species (ROS). It is critical to understand not only the triggers for hepatitis (injury and inflammation) in NASH but also how this is perpetuated as chronic liver disease. The present focus is on whether the biochemical processes that generate oxidative stress lead to hepatocyte injury and secondary recruitment of inflammation or whether inflammation is the primary mediator of liver cell injury. Insulin resistance is a reproducible pathogenic factor in NASH. It favors accumulation of free fatty acids in the liver and predisposes to oxidative stress by stimulating microsomal lipid peroxidases and by the direct effects of high insulin levels in decreasing mitochondrial beta-oxidation. CYP2E1 is normally suppressed by insulin but is invariably increased in the livers of patients with NASH. In rodent dietary models of steatohepatitis, CYP2E1 is the catalyst of microsomal lipid peroxidation, while in Cyp 2e1 nullizygous mice, CYP4A proteins are induced and function as alternative microsomal lipid peroxidases. Other studies implicate activation of peroxisome proliferator-activated receptor-alpha (PPAR alpha) as leading to NASH; PPAR alpha is a transcription factor that governs both microsomal (via CYP4A) and peroxisomal (beta-oxidation) pathways of lipid oxidation and ultimately production of ROS. Increased lipid peroxidation is a crucial difference between the livers of rodents with experimental NASH and those of ob/ob genetically obese mice that have uncomplicated steatosis. Administration of endotoxin, through the release of tumor necrosis factor-alpha (TNF-alpha), provokes liver inflammation with hepatocyte injury in the steatotic liver. This may be particularly relevant in JIB and has been suggested as a pathogenic mechanism in primary NASH. It has been proposed that inheriting one or more copies of the hemochromatosis gene, C282Y, promotes fibrotic progression in NASH because of increased hepatic iron deposition, but recent studies have failed to confirm this. The relationship between the severity of hepatitis in NASH and progression to cirrhosis implies that products of the inflammatory infiltrate play a role in fibrogenesis. In summary, NASH can be regarded as the hepatic consequence of the metabolic syndrome (or syndrome X). Attention should now shift from steatosis, a generally benign process that is less evident in the advanced stages of cirrhosis, to the mechanisms for hepatocellular injury, inflammation, and hepatic fibrosis. In particular, the genetic, molecular, and cellular factors that ordain and moderate fibrosis in the context of steatohepatitis will be of greatest relevance to effective therapy and clinical outcome.
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PMID:Etiopathogenesis of nonalcoholic steatohepatitis. 1129 94

Secondary hyperlipidemia is a major cardiovascular risk factor in individuals with type 2 diabetes. Increased hepatic production of apolipoprotein B (apoB)-containing lipoproteins contributes to the elevated plasma levels, but the mechanism is poorly understood. Recent results have established that microsomal triglyceride transfer protein (MTP) is rate limiting for the assembly and secretion of apoB-containing lipoproteins. To better understand the mechanism of type 2 diabetes-associated hyperlipidemia, we quantified hepatic MTP mRNA levels, hepatic microsomal triglyceride transfer activity, and in vivo triglyceride secretion from the liver in two diabetic mouse models. Obese diabetic (ob/ob) mice had 45% higher (P = 0.006) hepatic MTP mRNA levels, 54% higher (P < 0.0001) microsomal triglyceride transfer activity, and 70% higher (P < 0.0001) in vivo triglyceride secretion rates compared with ob/+ control mice. In contrast, in lean streptozotocin-treated diabetic mice, hepatic MTP mRNA levels were unchanged, whereas microsomal triglyceride transfer activity and in vivo triglyceride secretion rates were marginally decreased. These studies suggest that obesity-induced type 2 diabetes in mice confers increases in hepatic MTP expression and secretion of triglyceride-rich lipoproteins. High blood glucose and altered hepatic expression of sterol regulatory element binding protein genes play a minor role in this diabetic response.
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PMID:Hepatic expression of microsomal triglyceride transfer protein and in vivo secretion of triglyceride-rich lipoproteins are increased in obese diabetic mice. 1191 50

In humans, glucocorticoids are important regulators of adipose tissue distribution and function but circulating cortisol concentrations are normal in most patients with obesity. However, intracellular glucocorticoid levels can be modified by a microsomal enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) expressed mainly in the liver and adipose tissue. Locally generated cortisol within human adipose tissue can induce preadipocyte differentiation, but the relationship between 11beta-HSD1 expression and adipogenesis is unknown. Our present study has shown that in intact, undifferentiated omental (OM) but not subcutaneous (SC) preadipocytes, 11beta-HSD1 acts primarily as a dehydrogenase inactivating cortisol to cortisone. When preadipocytes become "committed" to adipocyte differentiation, oxo-reductase activity predominates generating cortisol. Since glucocorticoids are not only essential for OM preadipocyte differentiation but also inhibit cell proliferation, we postulate that 11beta-HSD1 dehydrogenase activity in "uncommitted" OM preadipocytes may provide an autocrine mechanism to protect preadipocytes from differentiation, in turn facilitating their proliferation. Once early differentiation is initiated, a "switch" to 11beta-HSD1 oxo-reductase activity generates cortisol, thus promoting adipogenesis. The differences in set-point of 11beta-HSD1 activity between OM and SC human adipose tissue may be an important factor in the pathogenesis of visceral obesity.
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PMID:11Beta-hydroxysteroid dehydrogenase type 1 in differentiating omental human preadipocytes: from de-activation to generation of cortisol. 1253 Jun 48

While human diets have markedly evolved since their origin, the human genome has only marginally changed. Nevertheless, polymorphisms of common genes are widespread. It has been substantiated that most major diseases (including cardiovascular disease, diabetes, obesity and cancers) result from the interaction between genetic susceptibility and environmental factors, including diet. In the field of lipoprotein metabolism and cardiovascular disease several gene polymorphisms for key proteins, such as apoproteins (apo) E, B, A-IV and C-III, LDL receptor, microsomal transfer protein (MTP), fatty acid-binding protein (FABP), cholesteryl ester transfer protein (CETP), lipoprotein lipase and hepatic lipase, have been identified and linked to variable responses to diets. We are carrying out an intervention study (RIVAGE) in Marseille dedicated to investigating the interactions between diets (Mediterranean or low-fat types v. standard Western type), risk factors for cardiovascular disease and gene polymorphisms in about 300 patients randomized into two groups over periods of 3 and 12 months. Some data obtained in about 100 patients after 3 months of dietary change are available. Among single nucleotide polymorphisms (SNP) already studied (apoE (epsilon2, epsilon3, epsilon4), apoB (-516C/T), apoC-III (SstI), apoA-IV (Ser347Thr), MTP (-493G/T), intestinal FABP (Ala54Thr), CETP (TaqIB) and hepatic lipase (-480C/T)), some SNP showed interactions with diets in relation to changes in particular variables after 3 months on the dietary regimens. This was the case for apoE and LDL-cholesterol and triacylglycerols, apoA-IV and LDL-cholesterol, MTP and LDL-cholesterol, intestinal FABP and triacylglycerols. These data provide evidence of the interaction between some SNP and the metabolic response to diets.
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PMID:Genetic polymorphisms and lipoprotein responses to diets. 1269 Nov 71

The purpose of this study was to determine if there were differences in the capacity of skeletal muscle from morbidly obese Black and White American women to oxidize fatty acids. The oxidation rates of (14)C-palmitate, (14)C-palmitoyl-CoA, and (14)C-palmitoyl-carnitine were measured in whole homogenates of rectus abdominus from Black and White women who were similar in age and body mass index (BMI). The activities of muscle citrate synthase (CS), beta-hydroxy acyl-CoA dehydrogenase (beta-HAD), and mitochondrial and microsomal acyl-CoA synthetase (ACS) were measured in the 2 groups. The results showed that the rate of (14)C-palmitate oxidation by muscle of Black women was 25% that of Whites (8.7 +/- 1.5 v 34.4 +/- 6.8 nmol (14)CO(2) produced/gram tissue wet weight/ hour; P <.05), but the rates of (14)C-palmitoyl-CoA and (14)C-palmitoyl-carnitine oxidation were not different in the 2 groups. No differences were found in the activities of CS or beta-HAD. However, the activities of both mitochondrial and microsomal ACS were lower in the Black women than the Whites (mitochondrial ACS 25.1 +/- 3.9 v 36.4 +/- 5.0 nmol/mg protein/min; P <.05; microsomal ACS 6.2 +/- 0.5 v 8.5 +/- 0.5; nmol/mg protein/min; P <.005). The lower rate of palmitate oxidation, and the lack of differences in the rates of palmitoyl-CoA and palmitoyl-carnitine oxidation indicate that there is a defect in the activation of the fatty acid in the muscle of the Black women. This was confirmed by the decrease in mitochondrial ACS activity in the Black women. The decreased fatty acid oxidation by skeletal muscle of obese Black women could result in shunting these fuels from muscle to adipose tissue for storage, which may contribute to the maintenance of obesity in the Black women.
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PMID:Fatty acid oxidation by skeletal muscle homogenates from morbidly obese black and white American women. 1280 Jan

Glycerol-3-phosphate acyltransferase (GPAT) catalyses the first committed step in glycerolipid biosynthesis. The mitochondrial isoform (mtGPAT) is mainly expressed in liver, where it is highly regulated, indicating that mtGPAT may have a unique role in hepatic fatty acid metabolism. Because both mtGPAT and carnitine palmitoyl transferase-1 are located on the outer mitochondrial membrane, we hypothesized that mtGPAT directs fatty acyl-CoA away from beta-oxidation and toward glycerolipid synthesis. Adenoviral-mediated overexpression of murine mtGPAT in primary cultures of rat hepatocytes increased mtGPAT activity 2.7-fold with no compensatory effect on microsomal GPAT activity. MtGPAT overexpression resulted in a dramatic 80% reduction in fatty acid oxidation and a significant increase in hepatic diacylglycerol and phospholipid biosynthesis. Following lipid loading of the cells, intracellular triacylglycerol biosynthesis was also induced by mtGPAT overexpression. Changing an invariant aspartic acid residue to a glycine [D235G] in mtGPAT resulted in an inactive enzyme, which helps define the active site required for mammalian mtGPAT function. To determine if obesity increases hepatic mtGPAT activity, two models of rodent obesity were examined and shown to have >2-fold increased enzyme activity. Overall, these results support the concept that increased hepatic mtGPAT activity associated with obesity positively contributes to lipid disorders by reducing oxidative processes and promoting de novo glycerolipid synthesis.
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PMID:Overexpression of mitochondrial GPAT in rat hepatocytes leads to decreased fatty acid oxidation and increased glycerolipid biosynthesis. 1510 85

Oxidation of ethanol via alcohol dehydrogenase (ADH) explains various metabolic effects of ethanol but does not account for the tolerance. This fact, as well as the discovery of the proliferation of the smooth endoplasmic reticulum (SER) after chronic alcohol consumption, suggested the existence of an additional pathway which was then described by Lieber and DeCarli, namely the microsomal ethanol oxidizing system (MEOS), involving cytochrome P450. The existence of this system was initially challenged but the effect of ethanol on liver microsomes was confirmed by Remmer and his group. After chronic ethanol consumption, the activity of the MEOS increases, with an associated rise in cytochrome P450, especially CYP2E1, most conclusively shown in alcohol dehydrogenase negative deer mice. There is also cross-induction of the metabolism of other drugs, resulting in drug tolerance. Furthermore, the conversion of hepatotoxic agents to toxic metabolites increases, which explains the enhanced susceptibility of alcoholics to the adverse effects of various xenobiotics, including industrial solvents. CYP2E1 also activates some commonly used drugs (such as acetaminophen) to their toxic metabolites, and promotes carcinogenesis. In addition, catabolism of retinol is accelerated resulting in its depletion. Contrasting with the stimulating effects of chronic consumption, acute ethanol intake inhibits the metabolism of other drugs. Moreover, metabolism by CYP2E1 results in a significant release of free radicals which, in turn, diminishes reduced glutathione (GSH) and other defense systems against oxidative stress which plays a major pathogenic role in alcoholic liver disease. CYP1A2 and CYP3A4, two other perivenular P450s, also sustain the metabolism of ethanol, thereby contributing to MEOS activity and possibly liver injury. CYP2E1 has also a physiologic role which comprises gluconeogenesis from ketones, oxidation of fatty acids, and detoxification of xenobiotics other than ethanol. Excess of these physiological substrates (such as seen in obesity and diabetes) also leads to CYP2E1 induction and nonalcoholic fatty liver disease (NAFLD), which includes nonalcoholic fatty liver and nonalcoholic steatohepatitis (NASH), with pathological lesions similar to those observed in alcoholic steatohepatitis. Increases of CYP2E1 and its mRNA prevail in the perivenular zone, the area of maximal liver damage. CYP2E1 up-regulation was also demonstrated in obese patients as well as in rat models of obesity and NASH. Furthermore, NASH is increasingly recognized as a precursor to more severe liver disease, sometimes evolving into "cryptogenic" cirrhosis. The prevalence of NAFLD averages 20% and that of NASH 2% to 3% in the general population, making these conditions the most common liver diseases in the United States. Considering the pathogenic role that up-regulation of CYP2E1 also plays in alcoholic liver disease (vide supra), it is apparent that a major therapeutic challenge is now to find a way to control this toxic process. CYP2E1 inhibitors oppose alcohol-induced liver damage, but heretofore available compounds are too toxic for clinical use. Recently, however, polyenylphosphatidylcholine (PPC), an innocuous mixture of polyunsaturated phosphatidylcholines extracted from soybeans (and its active component dilinoleoylphosphatidylcholine), were discovered to decrease CYP2E1 activity. PPC also opposes hepatic oxidative stress and fibrosis. It is now being tested clinically.
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PMID:The discovery of the microsomal ethanol oxidizing system and its physiologic and pathologic role. 1555 33

Apart from Na(+),K(+)-ATPase, a second sodium pump, Na(+)-stimulated, K(+)-independent ATPase (Na(+)-ATPase) is expressed in proximal convoluted tubule of the mammalian kidney. The aim of this study was to develop a method of Na(+)-ATPase assay based on the method previously used by us to measure Na(+),K(+)-ATPase activity. The ATPase activity was assayed as the amount of inorganic phosphate liberated from ATP by isolated microsomal fraction. Na(+)-ATPase activity was calculated as the difference between the activities measured in the presence and in the absence of 50 mM NaCl. Na(+)-ATPase activity was detected in the renal cortex (3.5 +/- 0.2 mumol phosphate/h per mg protein), but not in the renal medulla. Na(+)-ATPase was not inhibited by ouabain or an H(+),K(+)-ATPase inhibitor, Sch 28080, but was almost completely blocked by 2 mM furosemide. Leptin administered intraperitoneally (1 mg/kg) decreased the Na(+),K(+)-ATPase activity in the renal medulla at 0.5 and 1 h by 22.1% and 27.1%, respectively, but had no effect on Na(+)-ATPase in the renal cortex. Chronic hyperleptinemia induced by repeated subcutaneous leptin injections (0.25 mg/kg twice daily for 7 days) increased cortical Na(+),K(+)-ATPase, medullary Na(+),K(+)-ATPase and cortical Na(+)-ATPase by 32.4%, 84.2% and 62.9%, respectively. In rats with dietary-induced obesity, the Na(+),K(+)- ATPase activity was higher in the renal cortex and medulla by 19.7% and 34.3%, respectively, but Na(+)-ATPase was not different from control. These data indicate that both renal Na(+)-dependent ATPases are separately regulated and that up-regulation of Na(+)-ATPase may contribute to Na(+) retention and arterial hypertension induced by chronic hyperleptinemia.
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PMID:Spectrophotometric assay of renal ouabain-resistant Na(+)-ATPase and its regulation by leptin and dietary-induced obesity. 1562 72

MB243 (a 1,3-disubstituted piperazine) is a new, potent, and selective melanocortin receptor subtype-4 agonist with potential application in the treatment of obesity and/or erectile dysfunction. MB243 was observed to covalently bind extensively to liver microsomal proteins from rats and humans. In the presence of glutathione, two thioether adducts were detected in liver microsomal incubations by radiochromatography and LC/MS/MS analysis. These adducts were also formed when bile duct-cannulated rats were dosed with MB243. The two adducts were isolated, and their structures were determined by accurate mass MS/MS and NMR analyses. The proposed structures resulted from a novel contraction of the piperazine ring to yield a substituted imidazoline. A mechanism is proposed, which involves an initial six electron oxidation of the piperazine ring to form a reactive intermediate, which is trapped by glutathione. Hydrolysis of the glutamic acid residue followed by internal aminolysis by the cysteine amino group resulted in opening of the piperazine ring, which is followed by ring closure to an imidazoline. The resulting cysteinyl-glycine conjugate underwent subsequent hydrolysis of the glycine residue. Understanding of the mechanism of bioactivation led to the design of MB243 analogues that exhibited reduced covalent protein binding.
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PMID:Metabolic activation of a 1,3-disubstituted piperazine derivative: evidence for a novel ring contraction to an imidazoline. 1572 Jan 32

Sibutramine is an anti-obesity drug sold as a racemic mixture under the trademark Meridia or Reductil. With the aim of evaluating the stereoselectivity in phase I of sibutramine biotransformation, the formation of the main metabolites from R -sibutramine, S -sibutramine and rac-sibutramine was studied in rat microsomes and primary cultures of hepatocytes. A novel analytical method for the determination of sibutramine and its phase I metabolites in culture medium and microsomal incubates using isocratic reversed-phase liquid chromatography with UV detection was developed. Only two metabolites, mono-desmethylsibutramine (M1) and di-desmethylsibutramine (M2), were found in the rat microsomes incubated with sibutramine and NADPH. The kinetics of M1 and M2 formation slightly differed depending on the enantiomeric form of the sibutramine used. The stereoselectivity in sibutramine biotransformation was much more evident in primary cultures of rat hepatocytes. While R-sibutramine incubation led to the formation of M1 and M2 metabolites only, the incubation of S-sibutramine or rac-sibutramine (to a lesser extent) resulted in four major metabolites (M1, M2, M3 and M4) and 2 or 3 minor metabolites. On the basis of our results, R-sibutramine might represent the more advantageous sibutramine enantiomer from the pharmacokinetic standpoint.
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PMID:The stereoselective biotransformation of the anti-obesity drug sibutramine in rat liver microsomes and in primary cultures of rat hepatocytes. 1580 98


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