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)

Multifaceted evidence links the development of liver tumours to the activation and proliferation of adult liver progenitor (oval) cells during the early stages of chronic liver injury. The aim of this study was to examine the role of the peroxisome proliferator activated receptors (PPARs): PPARalpha, delta and gamma, in mediating the behaviour of liver progenitor cells during pre-neoplastic disease and to investigate their potential as therapeutic targets for the treatment of chronic liver injury. We observed increased liver expression of PPARalpha and gamma in concert with expanding oval cell numbers during the first 21 days following commencement of the choline deficient, ethionine supplemented (CDE) dietary model of carcinogenic liver injury in mice. Both primary and immortalized liver progenitor cells were found to express PPARalpha, delta and gamma, but not gamma2, the alternate splice form of PPARgamma. WY14643 (PPARalpha agonist), GW501516 (PPARdelta agonist) and ciglitazone (PPARgamma agonist) were tested for their ability to modulate the behaviour of p53-immortalized liver (PIL) progenitor cell lines in vitro. Both PPARdelta and gamma agonists induced dose-dependent growth inhibition and apoptosis of PIL cells. In contrast, the PPARalpha agonist had no effect on PIL cell growth. None of the drugs affected the maturation of PIL cells along either the hepatocytic or biliary lineages, as judged by their patterns of hepatic gene expression prior to and following treatment. Administration of the PPARgamma agonist ciglitazone to mice fed with the CDE diet for 14 days resulted in a significantly diminished oval cell response and decreased fibrosis compared with those receiving placebo. In contrast, GW501516 did not affect oval cell numbers or liver fibrosis, but inhibited CDE-induced hepatic steatosis. In summary, PPARgamma agonists reduce oval cell proliferation and fibrosis during chronic liver injury and may be useful in the prevention of hepatocellular carcinoma.
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PMID:Inhibition of adult liver progenitor (oval) cell growth and viability by an agonist of the peroxisome proliferator activated receptor (PPAR) family member gamma, but not alpha or delta. 1591 8

Administration of a choline-deficient, l-amino acid-defined (CDAA) diet to rats causes steatohepatitis, hepatic fibrosis, and hepatocellular carcinoma, a pathology similar to that observed in non-alcoholic steatohepatitis (NASH). The aim of this study was to evaluate if a peroxisome proliferator-activated receptor (PPAR)-gamma agonist, pioglitazone (PGZ), could ameliorate CDAA diet-induced fatty liver and cirrhosis. Rats were fed a CDAA diet for 1 week and were given the CDAA diet for an additional week with or without PGZ (2-week model). Also, after administration of the CDAA diet for 12 weeks, rats were administered the CDAA diet for an additional 4 weeks with or without PGZ (16-week model). The CDAA diet, administered for either one or 12 weeks, induced fatty liver or cirrhosis with up-regulation of hepatic PPAR-gamma expression, respectively. In the 2-week model, rats treated with PGZ for 1 week demonstrated significantly lower hepatic triglyceride content and serum levels of tumor necrosis factor-alpha. In the 16-week model, treatment for 4 weeks with PGZ ameliorated hepatic fibrosis with a decrease in the expression of procollagen, alpha-smooth muscle actin, and transforming growth factor-beta1 in comparison to rats without PGZ. These results suggest that PPAR-gamma agonist is a potential therapeutic modality to treat NASH.
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PMID:The peroxisome proliferator-activated receptor-gamma agonist, pioglitazone, inhibits fat accumulation and fibrosis in the livers of rats fed a choline-deficient, l-amino acid-defined diet. 1608 55

The protective effect of dietary saturated fatty acids against the development of alcoholic liver disease has long been known, but the underlying mechanism is not completely understood. We examined the involvement of the adipocyte hormone adiponectin. Circulating adiponectin levels were significantly elevated by chronic ethanol administration to mice consuming a diet high in saturated fat. The increase in circulating adiponectin was associated with the activation a set of hepatic signaling pathways mediated through AMP-activated protein kinase, PPAR-alpha, and PPAR-gamma coactivator alpha, which in turn led to markedly increased rates of fatty acid oxidation, prevention of hepatic steatosis, and alleviation of liver enzyme changes. Furthermore, treatment of rat 3T3-L1 adipocytes with saturated fatty acids (palmitic or stearic acids) in the presence of ethanol increased secretion of adiponectin and enhanced activity of a mouse adiponectin promoter. In conclusion, the protective action of saturated fat against the development of alcoholic fatty liver in mice is partially mediated through induction of adiponectin. The present findings suggest a novel paradigm for dietary fatty acids in the pathogenesis of alcoholic liver disease and provide a promising therapeutic strategy-nutritional modulation of adiponectin-in treating human alcoholic fatty liver disease.
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PMID:Role of adiponectin in the protective action of dietary saturated fat against alcoholic fatty liver in mice. 1611 27

This is the first report of the effects of a nonthiazolidinedione activator of peroxisome proliferator-activated receptor (PPAR) gamma, that is, FK-614 (a benzimidazole derivative), on glucose metabolism in vivo. To investigate the effect of FK-614 on peripheral and hepatic insulin action, we performed hyperinsulinemic-hyperglycemic clamp studies combined with the triple-catheter technique and a double-tracer approach in alloxan-diabetic dogs with (n=5) or without (n=6) treatment with FK-614 (0.32 mg/kg per day orally for 10 days). Throughout the experiment, insulin was infused intraportally at 18 pmol/kg per minute and hyperglycemia (approximately 11 mmol/L) was maintained by a peripheral glucose infusion. After a 45-minute basal period (period I), a portal infusion of glucose labeled with [U-14C]-glucose, was administered for 120 minutes (period II) to measure hepatic glucose uptake. This was followed by 90-minute recovery (period III). FK-614 marginally improved peripheral insulin sensitivity, did not affect hepatic glucose uptake, and surprisingly increased tracer-determined hepatic glucose production (19.0+/-5.0 vs 10.6+/-1.7 mumol/kg per minute, P<.001). Hepatic insulin extraction was decreased by FK-614 (47.8%+/-1.6% vs 55.9%+/-3.4%, P<.01), which led to greater peripheral insulin levels and glucose utilization. FK-614 treatment also decreased the daily insulin requirements (regular insulin, 0.18+/-0.01 vs 0.32+/-0.01 U/kg per day; and NPH insulin, 0.53+/-0.02 vs 0.89+/-0.04 U/kg per day; P<.001) to maintain fasting plasma glucose at approximately 10 mmol/L for 7 days before the experiments. We conclude that FK-614 treatment, at the dose used, improves peripheral glucose utilization because of an improvement in peripheral insulin sensitivity and a decrease in insulin clearance, but impairs hepatic insulin action in alloxan-induced diabetic dogs. The reason for the effects of FK-614 on hepatic glucose and insulin metabolism is unclear but they are both consistent with reports of hepatic steatosis by PPARgamma activation when unopposed by concomitant activation of PPARalpha.
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PMID:FK-614, a selective peroxisome proliferator-activated receptor gamma agonist, improves peripheral glucose utilization while decreasing hepatic insulin extraction in alloxan-induced diabetic dogs. 1612 38

The present study was performed to examine a hypothesis that peroxisome proliferator-activated receptor gamma (PPARgamma) is implicated in high fat diet-induced liver steatosis. Mice were fed with control or high fat diet containing approximately 10% or 80% cholesterol, respectively. Macroscopic and microscopic findings demonstrated that lipid accumulation in the liver was observed as early as 2 weeks after high fat diet and that high fat diet for 12 weeks developed a fatty liver phenotype, establishing a novel model of diet-induced liver steatosis. Gene profiling with microarray and real-time PCR studies demonstrated that among genes involved in lipid metabolism, adipogenesis-related genes, PPARgamma and its targeted gene, CD36 mRNA expression was specifically up-regulated in the liver by high fat diet for 2 weeks. Immunohistochemical study revealed that PPARgamma protein expression is increased in the nuclei of hepatocytes by high fat diet. It was also shown that protein expression of cAMP response element-binding protein (CREB), an upstream molecule of PPARgamma, in the liver was drastically suppressed by high fat diet. All these results suggest for the first time that the CREB-PPARgamma signaling pathway may be involved in the high fat diet-induced liver steatosis.
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PMID:Increased expression of PPARgamma in high fat diet-induced liver steatosis in mice. 1612 73

Essential polyunsaturated fatty acids (PUFAs), linoleic acid n6 (LA) and linolenic acid (ALA) n3 obtained from the diet are precursors of the long-chain polyunsaturated fatty acids (Lc-PUFAs) arachidonic acid (AA) and docosahexaenoic acid (DHA) respectively. Consumption of PUFAs is related with a better neurological and cognitive development in newborns. It has been demonstrated that consumption of n-6 and n-3 PUFAs decreases blood triglycerides by increasing fatty acid oxidation through activation of PPARalpha or by reducing the activation of SREBP-1 inhibiting lipogenesis. Dietary PUFAs activate PPARalpha and PPARgamma increasing lipid oxidation, and decreasing insulin resistance leading in a reduction of hepatic steatosis. Beneficial effects of PUFAs have been observed in humans and in animals models of diabetes, obesity, cancer, and cardiovascular diseases. It is important to promote the consumption of PUFAs. Main food sources of PUFAs n-6 are corn, soy and safflower oil, and for PUFAs n-3 are fish, soy, canola oil and, flaxseed. Finally FAO/WHO recommends an optimal daily intake of n6/n3 of 5-10:1.
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PMID:[Molecular mechanisms of action and health benefits of polyunsaturated fatty acids]. 1618 7

The present study was performed to examine a role of adipose differentiation-related protein (ADRP) in the process of liver steatosis. Immunohistochemical findings indicated that ADRP expression is increased in the hepatocytes in patients with fatty liver when compared with normal liver. ADRP expression is localized in the surface of lipid droplets in the hepatocytes. Increased expression of ADRP mRNA and protein was similarly observed in fatty liver in ob/ob mice and the liver steatosis induced by high fat diet in mice. The up-regulation of ADRP mRNA and protein in the liver by high fat diet was identified in the surface of lipid droplets in a time-dependent manner. Recent studies demonstrated that up-regulation of PPARgamma in the hepatocytes is deeply involved in liver steatosis. To clarify whether ADRP expression is increased by PPARgamma activation in hepatocytes, we examined the effect of a PPARgamma ligand, troglitazone, on ADRP mRNA expression in HepG2 cells. ADRP mRNA expression was increased by troglitazone in dose- and time-dependent manners. All these results suggest that ADRP is up-regulated in liver steatosis in human and mice, and that high fat diet increases expression of ADRP through PPARgamma activation, followed by induction of liver steatosis.
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PMID:Up-regulation of ADRP in fatty liver in human and liver steatosis in mice fed with high fat diet. 1640 37

Selective loss of body fat is the hallmark of patients with lipodystrophies. Among genetic lipodystrophies, fat loss is observed either from birth, as in congenital generalized lipodystrophy, or later in life, as in familial partial lipodystrophy. The extent of fat loss also varies among subtypes of lipodystrophies. Patients develop hyperinsulinemia, acanthosis nigricans, hypertriglyceridemia, diabetes mellitus, and hepatic steatosis. Defects in several genes, such as those encoding an enzyme (AGPAT2), a nuclear receptor (PPARgamma), a nuclear lamina protein (LMNA) and its processing endoprotease (ZMPSTE24), a kinase (AKT2), and a protein of unknown function (BSCL2), have been found in patients with genetic lipodystrophies. Additional loci remain to be discovered. We discuss features of autosomal recessive and dominant types of lipodystrophies and therapeutic interventions available for these patients.
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PMID:Genetic basis of lipodystrophies and management of metabolic complications. 1640 51

Insulin resistance is an integral part of the underlying pathophysiology in most patients with nonalcoholic fatty liver disease (NAFLD). Insulin-sensitizing agents are therefore likely to be of key importance in the treatment of this disorder, especially in the histologically more severe form known as nonalcoholic steatohepatitis. Here we have reviewed the current literature on the two major insulin-sensitizing agents that have been studied in patients with NAFLD: the thiazolidinediones (or PPAR-gamma agonists) and metformin, the only available biguanide. Thiazolidinedione administration in human NAFLD has been shown to decrease hepatic fat by several different global measures and to decrease evidence of cellular injury, but it has also been associated with increased peripheral fat and weight gain. In contrast, metformin has been shown to improve biochemical markers without weight gain, but with more variable improvement in histology. Neither agent has been FDA approved for treating NAFLD, but existing studies have provided much hope for incorporating these medications into NAFLD management strategies in selected patients.
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PMID:Therapy of NAFLD: insulin sensitizing agents. 1654 Jul 70

Insulin resistance is an integral part of the underlying pathophysiology in most patients with nonalcoholic fatty liver disease (NAFLD). Insulin-sensitiziting agents are therefore likely to be of key importance in the treatment of this disorder, especially in the histologically more severe form known as nonalcoholic steatohepatitis. Here we have reviewed the current literature on the two major insulin-sensitizing agents that have been studied in patients with NAFLD: the thiazolidinediones (or PPAR-gamma agonists) and metformin, the only available biguanide. Thiazolidinedione administration in human NAFLD has been shown to decrease hepatic fat by several different global measures and to decrease evidence of cellular injury, but it has also been associated with increased peripheral fat and weight gain. In contrast, metformin has been shown to improve biochemical markers without weight gain, but with more variable improvement in histology. Neither agent has been FDA approved for treating NAFLD, but existing studies have provided much hope for incorporating these medications into NAFLD management strategies in selected patients.
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PMID:Therapy of NAFLD: Insulin Sensitizing Agents. 1667 28


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