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)

Adiponectin protects the liver from steatosis caused by obesity or alcohol and therefore the influence of adiponectin on human hepatocytes was analyzed. GeneChip experiments indicated that recombinant adiponectin downregulates aldehyde oxidase 1 (AOX1) expression and this was confirmed by real-time RT-PCR and immunoblot. AOX1 is a xenobiotic metabolizing protein and produces reactive oxygen species (ROS), that promote cell damage and fibrogenesis. Adiponectin and fenofibric acid activate peroxisome proliferator-activated receptor-alpha (PPAR-alpha) and both suppress AOX1 protein and this is blocked by the PPAR-alpha antagonist RU486. Obesity is associated with low adiponectin, reduced hepatic PPAR-alpha activity and fatty liver, and AOX1 was found induced in the liver of rats on a high-fat diet when compared to controls. Free fatty acids and leptin, that are elevated in obesity, failed to upregulate AOX1 in vitro. The current data indicate that adiponectin reduces AOX1 by activating PPAR-alpha whereas fatty liver disease is associated with elevated hepatic AOX1. High AOX1 may be associated with higher ROS well described to induce fibrogenesis in liver tissue but may also influence drug metabolism and activity.
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PMID:Aldehyde oxidase 1 is highly abundant in hepatic steatosis and is downregulated by adiponectin and fenofibric acid in hepatocytes in vitro. 1702 44

To determine the relative contribution of obesity and visceral white adipose tissue (WAT) to metabolic syndrome, we developed a model that is susceptible to high-fat diet-induced obesity and insulin resistance using male KK/Ta mice. The ratio of WAT weight to body weight was greater in the high-fat diet group compared with the control group in 10-, 14-, and 22-week-old mice. The increase in visceral WAT preceded development of fatty liver and insulin resistance. Adiponectin mRNA expression in WAT was markedly decreased before the decrease in its plasma levels or the development of insulin resistance. Insulin resistance appeared in association with fatty infiltration and TNF-alpha expression in the liver in 22-week-old mice. These data indicate that our mouse model would be useful for future studies that investigate the role of visceral WAT and its products in the development of metabolic syndrome.
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PMID:A Mouse Model of Metabolic Syndrome; Increase in Visceral Adipose Tissue Precedes the Development of Fatty Liver and Insulin Resistance in High-Fat Diet-Fed Male KK/Ta Mice. 1838 33

The relationship between insulin resistance and mitochondrial function is of increasing interest. Studies looking for such interactions are usually made in muscle and only a few studies have been done in liver, which is known to be a crucial partner in whole body insulin action. Recent studies have revealed a similar mechanism to that of muscle for fat-induced insulin resistance in liver. However, the exact mechanism of lipid metabolites accumulation in liver leading to insulin resistance is far from being elucidated. One of the hypothetical mechanisms for liver steatosis development is an impairment of mitochondrial function. We examined mitochondrial function in fatty liver and insulin resistance state using isolated mitochondria from obese Zucker rats. We determined the relationship between ATP synthesis and oxygen consumption as well as the relationship between mitochondrial membrane potential and oxygen consumption. In order to evaluate the quantity of mitochondria and the oxidative capacity we measured citrate synthase and cytochrome c oxidase activities. Results showed that despite significant fatty liver and hyperinsulinemia, isolated liver mitochondria from obese Zucker rats display no difference in oxygen consumption, ATP synthesis, and membrane potential compared with lean Zucker rats. There was no difference in citrate synthase and cytochrome c oxidase activities between obese and lean Zucker rats in isolated mitochondria as well as in liver homogenate, indicating a similar relative amount of hepatic mitochondria and a similar oxidative capacity. Adiponectin, which is involved in bioenergetic homeostasis, was increased two-fold in obese Zucker rats despite insulin resistance. In conclusion, isolated liver mitochondria from lean and obese insulin-resistant Zucker rats showed strictly the same mitochondrial function. It remains to be elucidated whether adiponectin increase is involved in these results.
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PMID:Fatty liver and insulin resistance in obese Zucker rats: no role for mitochondrial dysfunction. 1853 99

Worldwide, one of the most prevalent forms of chronic disease is alcoholic fatty liver, which may progress to more severe forms of liver injury including steatohepatitis, fibrosis, and cirrhosis. The molecular mechanisms by which ethanol consumption causes accumulation of hepatic lipid are multiple and complex. Chronic ethanol exposure is thought to cause enhanced hepatic lipogenesis and impaired fatty acid oxidation by inhibiting key hepatic transcriptional regulators such as AMP-activated kinase (AMPK), sirtuin 1 (SIRT1), PPAR-gamma coactivator alpha (PGC-1alpha), peroxisome proliferator-activated receptor alpha (PPARalpha), and sterol regulatory element-binding protein 1 (SREBP-1). Adiponectin is an adipose-derived hormone with a variety of beneficial biological functions. Increasing evidence suggests that altered adiponectin production in adipose tissue and impaired expression of hepatic adiponectin receptors (AdipoRs) are associated with the development of alcoholic liver steatosis in several rodent models. More importantly, studies have demonstrated a protective role of adiponectin against alcoholic liver steatosis. The hepato-protective effect of adiponectin is largely mediated by the coordination of multiple signaling pathways in the liver, leading to enhanced fat oxidation, reduced lipid synthesis and prevention of hepatic steatosis. This review begins with an assessment of the current understanding of the role of adiponectin and its receptors in the regulation of lipid homeostasis in liver, with emphasis on their relationship to the development of alcoholic liver steatosis. Following sections will review hepatic signaling molecules involved in the protective actions of adiponectin against alcoholic fatty liver and summarize the current knowledge of regulatory mechanisms of adiponectin expression and secretion in response to chronic ethanol exposure. We will conclude with a discussion of potential strategies for treating human alcoholic fatty liver disease (AFLD), including nutritional and pharmacological modulation of adiponectin and its receptors.
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PMID:Adiponectin and alcoholic fatty liver disease. 1870 50

Nonalcoholic steatohepatitis (NASH) is the hepatic manifestation of the metabolic syndrome. Currently, there is no established therapy for NASH. The aim of the present study was to evaluate the efficacy of atorvastatin in the treatment of NASH associated with hyperlipidemia. This prospective study included 31 patients with biopsy-proven NASH with hyperlipidemia. Body mass index, serum lipids, liver function tests, fibrosis markers, and adipocytokines (adiponectin, leptin, tumor necrosis factor-alpha) were measured periodically during an open-label study of atorvastatin (10 mg daily) for 24 months. Standard weight-loss counseling was continued during the treatment period. Oral glucose tolerance test and liver density assessed by computerized tomography were performed before and after treatment. Follow-up liver biopsy was performed in 17 patients. All 31 patients had high cholesterol levels at baseline, and 20 also presented high triglyceride levels. The body mass index and serum glucose levels did not change during the treatment. After treatment, 23 patients (74.2%) presented normal transaminase levels. Adiponectin levels were significantly increased, and the levels of tumor necrosis factor-alpha were significantly decreased. However, leptin levels were not changed significantly. The concentration of long-chain fatty acids was decreased; and significant decreases were observed in C18:2,n-6 (linoleic acid, -21%) and C20:4,n-6 (arachidonic acid, -22%). Liver steatosis and nonalcoholic fatty liver disease activity score were significantly improved, whereas 4 patients had increased fibrosis stage. The NASH-related metabolic parameters improved with therapy, including fibrosis in some patients. However, 4 of 17 patients had progression of fibrosis over the 2-year period, with 3 of them progressing to stage 3. It is unclear whether this divergent response represents sampling error, heterogeneity in the population, or untreated postprandial hyperglyceridemia. Controlled trials are needed to further investigate and resolve this.
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PMID:Efficacy of atorvastatin for the treatment of nonalcoholic steatohepatitis with dyslipidemia. 1901 95

Alcoholic fatty liver is a potentially pathologic condition which can progress to steatohepatitis, fibrosis, and cirrhosis if alcohol consumption is continued. Alcohol exposure may induce fatty liver by increasing NADH/NAD(+) ratio, increasing sterol regulatory element-binding protein-1 (SREBP-1) activity, decreasing peroxisome proliferator-activated receptor-alpha (PPAR-alpha) activity, and increasing complement C3 hepatic levels. Alcohol may increase SREBP-1 activity by decreasing the activities of AMP-activated protein kinase and sirtuin-1. Tumor necrosis factor-alpha (TNF-alpha) produced in response to alcohol exposure may cause fatty liver by up-regulating SREBP-1 activity, whereas betaine and pioglitazone may attenuate fatty liver by down-regulating SREBP-1 activity. PPAR-alpha agonists have potentials to attenuate alcoholic fatty liver. Adiponectin and interleukin-6 may attenuate alcoholic fatty liver by up-regulating PPAR-alpha and insulin signaling pathways while down-regulating SREBP-1 activity and suppressing TNF-alpha production. Recent studies show that paracrine activation of hepatic cannabinoid receptor 1 by hepatic stellate cell-derived endocannabinoids also contributes to the development of alcoholic fatty liver. Furthermore, oxidative modifications and inactivation of the enzymes involved in the mitochondrial and/or peroxisomal beta-oxidation of fatty acids could contribute to fat accumulation in the liver.
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PMID:Molecular mechanisms of alcoholic fatty liver. 1903 84

Adipose tissue is critical in energy homeostasis. Adipose tissue 'buffers' the lipids and energy rich compounds which are pumped into the blood stream soon after meals. It senses, signals other organs like liver and brain about the energy reserves via adipokines. Adiponectin, the most abundant adipokine has insulin sensitizing, anti-inflammatory antiatherogenic and antisteatotic effects. Adipose tissue dysfunction is accompanied by abnormal lipid distribution and storage which contributes to diseases like diabetes, nonalcoholic fatty liver disease and atherosclerosis. Obesity and lipodystrophy are associated with dysfunctional adipocytes. Pre-adipocytes are easy to isolate and culture. A personalized depot specific liposuction to remove the inactive adipocytes followed by adipocyte repopulation could be useful in the treatment of these diseases.
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PMID:Adipose tissue transplantation may be a potential treatment for diabetes, atherosclerosis and nonalcoholic steatohepatitis. 1904 21

Adiponectin is an insulin-sensitizing adipokine possessing multiple beneficial effects on obesity-related medical complications. This adipokine is secreted from adipocytes into the circulation as three oligomeric isoforms, including trimer, hexamer and the high molecular weight (HMW) oligomeric complex. Each oligomeric isoform of adiponectin possesses distinct biological properties and activates different signaling pathways in various target tissues. The hepato-protective activities have been demonstrated by many clinical and experimental studies. The decreased level of serum adiponectin represents an independent risk factor for nonalcoholic fatty liver disease (NAFLD) and liver dysfunctions in humans. In animals, elevation of circulating adiponectin by either pharmacological or genetic approaches leads to a significant alleviation of hepatomegaly, steatosis and necro-inflammation associated with various liver diseases. In adiponectin knockout mice, there is a pre-existing condition of hepatic steatosis and mitochondria dysfunction, which might contribute to the increased vulnerabilities of these mice to the secondary liver injuries induced by obesity and other conditions. This review aims to summarize recent advances on delineation of the structural, molecular and cellular mechanisms underlying the hepato-protective properties of adiponectin.
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PMID:Protective roles of adiponectin in obesity-related fatty liver diseases: mechanisms and therapeutic implications. 1946 13

Liver regeneration is a very complex and well-orchestrated process associated with signaling cascades involving cytokines, growth factors, and metabolic pathways. Adiponectin is an adipocytokine secreted by mature adipocytes, and its receptors are widely distributed in many tissues, including the liver. Adiponectin has direct actions in the liver with prominent roles to improve hepatic insulin sensitivity, increase fatty acid oxidation, and decrease inflammation. To test the hypothesis that adiponectin is required for normal progress of liver regeneration, 2/3 partial hepatectomy (PH) was performed on wild-type and adiponectin-null mice. Compared to wild-type mice, adiponectin-null mice displayed decreased liver mass regrowth, impeded hepatocyte proliferation, and increased hepatic lipid accumulation. Gene expression analysis revealed that adiponectin regulated the gene transcription related to lipid metabolism. Furthermore, the suppressed hepatocyte proliferation was accompanied with reduced signal transducer and activator of transcription protein 3 (STAT3) activity and enhanced suppressor of cytokine signaling 3 (Socs3) transcription. In conclusion, adiponectin-null mice exhibit impaired liver regeneration and increased hepatic steatosis. Increased expression of Socs3 and subsequently reduced activation of STAT3 in adiponectin-null mice may contribute to the alteration of the liver regeneration capability and hepatic lipid metabolism after PH.
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PMID:Adiponectin deficiency impairs liver regeneration through attenuating STAT3 phosphorylation in mice. 1956 44

The complexity pathogenesis in the nonalcoholic fatty liver disease (NAFLD) involves an interplay between adipokines and neuroendocrine regulation of energy balance, including the role of neuropeptide Y (NPY)/agouti-related protein (AgRP) system. The first aim of this study was to assess the effect of long-term interdisciplinary intervention on NAFLD in obese adolescents, and the second objective was to establish the relationship between NPY/AgRP ratio and adiponectinemia. Fifty-five postpuberty obese adolescents were submitted to interdisciplinary intervention. The group was divided between subjects with and without NAFLD (n = 19 and 36, respectively). Blood samples were collected to measure glycemia, hepatic transaminases, lipid profile, insulin resistance, and sensitivity. Adiponectin, NPY, and AgRP concentrations were measured by enzyme-linked immunosorbent assay. Food intake was measured using 3-day diet records. It was observed at baseline that important clinical parameters including body weight, body mass index, visceral fat, homeostasis model assessment of insulin resistance, quantitative insulin sensitivity check index, triglycerides, very low-density lipoprotein cholesterol, and hepatic transaminases were more altered in NAFLD patients. After the intervention, these parameters, total energy, and macronutrient intake were reduced significantly in both groups. The most important finding was the positive correlation between AgRP and visceral fat in all patients and the negative correlation between NPY/AgRP and adiponectinemia only in NAFLD obese adolescents. The NAFLD patients presented more altered clinical parameters than the non-NAFLD subjects, including the negative correlation between adiponectinemia and NPY/AgRP. These results suggested that NAFLD obese adolescents presented an inflammatory profile that can influence the neuroendocrine regulation of energy balance, suggesting an additional impairment in the weight loss therapy.
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PMID:Negative correlation between neuropeptide Y/agouti-related protein concentration and adiponectinemia in nonalcoholic fatty liver disease obese adolescents submitted to a long-term interdisciplinary therapy. 1994 38


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