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)

Leptin and adiponectin, the main metabolic products of adipose tissue, have been implicated in a wide spectrum of human diseases. Given the frequent presence of hepatic steatosis in several chronic liver diseases, there is currently increasing interest in the role of these adipokines in the development of hepatic steatosis and also in necroinflammation and fibrosis, mostly in patients with nonalcoholic fatty liver disease or chronic hepatitis C. According to experimental data, reduced adiponectin levels and increased leptin levels associated with leptin resistance, which are usually observed in obese patients with or without metabolic syndrome, may result in fat accumulation in the liver and in the enhancement of liver inflammation and mostly fibrogenesis. Increased leptin and decreased adiponectin serum levels have been detected initially in patients with nonalcoholic steatohepatitis and more recently in patients with chronic hepatitis C compared to healthy controls in most but not all studies, while the data on the associations between these adipokine levels and the severity of hepatic steatosis or fibrosis are still rather conflicting. However, several potential confounding parameters were not evaluated in all studies. Therefore, the associations between adipokines and liver histological lesions and their effects on liver cells should be evaluated further in prospective, carefully designed studies, including larger cohorts of patients with detailed assessment of metabolic and other potential confounding factors.
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PMID:The evolving role of leptin and adiponectin in chronic liver diseases. 1695 81

CCAAT/enhancer-binding protein beta (C/EBPbeta) plays a key role in initiation of adipogenesis in adipose tissue and gluconeogenesis in liver; however, the role of C/EBPbeta in hepatic lipogenesis remains undefined. Here we show that C/EBPbeta inactivation in Lepr(db/db) mice attenuates obesity, fatty liver, and diabetes. In addition to impaired adipogenesis, livers from C/EBPbeta(-/-) x Lepr(db/db) mice had dramatically decreased triglyceride content and reduced lipogenic enzyme activity. C/EBPbeta deletion in Lepr(db/db) mice down-regulated peroxisome proliferator-activated receptor gamma2 (PPARgamma2) and stearoyl-CoA desaturase-1 and up-regulated PPARalpha independent of SREBP1c. Conversely, C/EBPbeta overexpression in wild-type mice increased PPARgamma2 and stearoyl-CoA desaturase-1 mRNA and hepatic triglyceride content. In FAO cells, overexpression of the liver inhibiting form of C/EBPbeta or C/EBPbeta RNA interference attenuated palmitate-induced triglyceride accumulation and reduced PPARgamma2 and triglyceride levels in the liver in vivo. Leptin and the anti-diabetic drug metformin acutely down-regulated C/EBPbeta expression in hepatocytes, whereas fatty acids up-regulate C/EBPbeta expression. These data provide novel evidence linking C/EBPbeta expression to lipogenesis and energy balance with important implications for the treatment of obesity and fatty liver disease.
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PMID:CCAAT/enhancer-binding protein beta deletion reduces adiposity, hepatic steatosis, and diabetes in Lepr(db/db) mice. 1738 71

Obesity and insulin resistance are the key factors for progression of hepatic fibrosis in various chronic liver diseases including non-alcoholic steatohepatitis (NASH). Recently it has been shown that leptin plays a pivotal role in development of hepatic fibrosis. Leptin promotes hepatic fibrogenesis through upregulation of transforming growth factor-beta in Kupffer cells and sinusoidal endothelial cells. Further, leptin facilitates proliferation and prevents apoptosis of hepatic stellate cells. There is a paradox, however, in that ob/ob mice and Zucker rats, which are the obese and diabetic strains, had minimal profibrogenic responses in the liver, most likely because they lack leptin and its receptors. To establish a more clinically relevant model to study the mechanism of fibrogenesis under steatohepatitis, fatty changes and profibrogenic responses in the liver caused by methionine-choline deficiency (MCD) were investigated in the KK-A(y) mouse, which is an obese and diabetic strain. KK-A(y) mice developed more severe hepatic steatosis, inflammation and fibrosis induced by an MCD diet as compared to C57Bl/6 controls. Importantly, KK-A(y) mice lack physiological upregulation of adiponectin levels, suggesting that adiponectin plays a pivotal role not only in regulation of insulin sensitivity but also in modulation of inflammatory and profibrogenic responses in dietary steatohepatitis. Collectively, these findings support the hypothesis that the balance of adipocytokine expression is a key regulator for the progression of hepatic fibrosis in the setting of steatohepatitis.
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PMID:Role of adipocytokines in hepatic fibrogenesis. 1756 76

Progenitors regenerate fatty livers but the mechanisms involved are uncertain. The Hedgehog pathway regulates mesendodermal progenitors and modulates mesenchymal-epithelial interactions during tissue remodeling. To determine if Hedgehog signaling increases in liver progenitors during fatty liver injury, we compared expression of Hedgehog ligands and target genes across a spectrum of injury. Leptin-deficient ob/ob mice with fatty livers and their healthy lean littermates were studied before and after exposure to the hepatotoxin, ethionine. At baseline, ob/ob mice had greater liver damage than controls. Ethionine induced liver injury in both ob/ob and lean mice, with greater injury occurring in ob/ob mice. After ethionine, the ob/ob mice developed liver atrophy and fibrosis. Liver injury increased hepatic accumulation of progenitors, including ductular cells that produced and responded to Hedgehog ligands. A dose-response relationship was demonstrated between liver injury and expansion of Hedgehog-responsive progenitors. In severely damaged, atrophic livers, nuclei in mature-appearing hepatocytes accumulated the Hedgehog-regulated mesenchymal transcription factor, Gli2 and lost expression of the liver epithelial transcription factor, hepatocyte nuclear factor 6 (HNF-6). Hepatic levels of collagen mRNA and pericellular collagen fibrils increased concomitantly. Hence, fatty liver injury increases Hedgehog activity in liver progenitors, and this might promote epithelial-mesenchymal transitions that result in liver fibrosis.
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PMID:Hepatic accumulation of Hedgehog-reactive progenitors increases with severity of fatty liver damage in mice. 1795 94

Leptin, an adipocyte-derived hormone, has emerged as a critical regulator of energy homeostasis. The leptin receptor (Lepr) is expressed in discrete regions of the brain; among the sites of highest expression are several mediobasal hypothalamic nuclei known to play a role in energy homeostasis, including the arcuate nucleus, the ventromedial hypothalamic nucleus (VMH), and the dorsomedial hypothalamic nucleus. Although most studies have focused on leptin's actions in the arcuate nucleus, the role of Lepr in these other sites has received less attention. To explore the role of leptin signaling in the VMH, we used bacterial artificial chromosome transgenesis to target Cre recombinase to VMH neurons expressing steroidogenic factor 1, thereby inactivating a conditional Lepr allele specifically in steroidogenic factor 1 neurons of the VMH. These knockout (KO) mice, designated Lepr KO(VMH), exhibited obesity, particularly when challenged with a high-fat diet. On a low-fat diet, Lepr KO(VMH) mice exhibited significantly increased adipose mass even when their weights were comparable to wild-type littermates. Furthermore, these mice exhibited a metabolic syndrome including hepatic steatosis, dyslipidemia, and hyperleptinemia. Lepr KO(VMH) mice were hyperinsulinemic from the age of weaning and eventually developed overt glucose intolerance. These data define nonredundant roles of the Lepr in VMH neurons in energy homeostasis and provide a model system for studying other actions of leptin in the VMH.
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PMID:Selective loss of leptin receptors in the ventromedial hypothalamic nucleus results in increased adiposity and a metabolic syndrome. 1825 79

The growing population of overweight humans threatens both industrialized and developing countries and has been accompanied by obesity-related disorders, including type II diabetes, hypertension, cardiovascular pathology and nonalcoholic fatty liver disease. Recent researches have demonstrated that intestinal microbiota may be associated with the host's obesity. There were researches on the interaction between Bacteroides thetaiotaomicron and the energy metabolism of the host. Methanobrevibacer smithii had been improved to impact the host's energy metabolism through modulating the gene transcription of B. thetaiotaomicron. The microbiota can direct the host to increase hepatic production of triglycerides, promote storage of triglycerides in adipocytes through suppression of intestinal expression of a circulating LPL inhibitor, and have an effect on the host's energy deposition through the interaction with host's hormones (eg. Leptin) . Some metabolic products of the microbiota like SCFAs, other organic acids, alcohols and gases can be used by the host directly. Researches mentioned above are just started. According to the results above, some key points remain unknown. For example, the underlying mechanism of the interaction between microbiota or some unique microbes and the host, the procedure of dietary polysaccharides degradation of the microbes, and the relationship between the microbiota and the host's hormones. In this paper, the corresponding research results of author' s lab has also been reviewed and the future research prospect s have been summarized.
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PMID:[The intestinal microbiota and obesity of the host]. 1827 Dec 77

Partial leptin deficiency is not uncommon in the general population. We hypothesized that leptin insufficiency could favor obesity, nonalcoholic steatohepatitis (NASH), and other metabolic abnormalities, particularly under high calorie intake. Thus, mice partially deficient in leptin (ob/+) and their wild-type (+/+) littermates were fed for 4 mo with a standard-calorie (SC) or a high-calorie (HC) diet. Some ob/+ mice fed the HC diet were also treated weekly with leptin. Our results showed that, when fed the SC diet, ob/+ mice did not present significant metabolic abnormalities except for elevated levels of plasma adiponectin. Under high-fat feeding, increased body fat mass, hepatic steatosis, higher plasma total cholesterol, and glucose intolerance were observed in +/+ mice, and these abnormalities were further enhanced in ob/+ mice. Furthermore, some metabolic disturbances, such as blunted plasma levels of leptin and adiponectin, reduced UCP1 expression in brown adipose tissue, increased plasma liver enzymes, beta-hydroxybutyrate and triglycerides, and slight insulin resistance, were observed only in ob/+ mice fed the HC diet. Whereas de novo fatty acid synthesis in liver was decreased in +/+ mice fed the HC diet, it was disinhibited in ob/+ mice along with the restoration of the expression of several lipogenic genes. Enhanced expression of several genes involved in fatty acid oxidation was also observed only in ob/+ animals. Leptin supplementation alleviated most of the metabolic abnormalities observed in ob/+ fed the HC diet. Hence, leptin insufficiency could increase the risk of obesity, NASH, glucose intolerance, and hyperlipidemia in a context of calorie overconsumption.
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PMID:Partial leptin deficiency favors diet-induced obesity and related metabolic disorders in mice. 1834 16

The metabolic effects of leptin may involve both centrally and peripherally mediated actions with a component of the central actions potentially independent of alterations in food intake. Ob/ob mice have significant abnormalities in lipid metabolism, correctable by leptin administration. We used ob/ob mice to study the relative importance of the subtypes of actions of leptin (central vs. peripheral; food intake dependent vs. independent) on lipid metabolism. Mice were treated for 3 d with leptin, either centrally [intracerebroventricular (icv)] or peripherally (ip), and compared with mice pair-fed to the leptin-treated mice (PF) and with ad libitum-fed controls (C). All treatment groups (icv, ip, PF) showed indistinguishable changes in liver weight; hepatic steatosis; hepatic lipidemic profile; and circulating free fatty acids, triglycerides, and cholesterol lipoprotein profile. Changes in the expression of genes involved in lipogenesis and fatty acid oxidation in liver, muscle, and white fat were broadly similar in ip, icv, and PF groups. Leptin (both icv and ip) stimulated expression of both mitochondrial and peroxisomal acyl-coenzyme A oxidase (liver) and peroxisomal proliferator-activated receptor-alpha (skeletal muscle) to an extent not replicated by pair feeding. Leptin had profound effects on peripheral lipid metabolism, but the majority were explained by its effects on food intake. Leptin had additional centrally mediated effects to increase the expression of a limited number of genes concerned with fatty acid oxidation. Whereas we cannot exclude direct peripheral effects of leptin on certain aspects of lipid metabolism, we were unable to detect any such effects on the parameters measured in this study.
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PMID:Leptin regulates peripheral lipid metabolism primarily through central effects on food intake. 1863 58

Leptin and insulin resistance are being discussed to be involved in the pathogenesis of nonalcoholic fatty liver disease, which is frequently characterized by moderately elevated transaminases. However, longitudinal studies proving an association between leptin, insulin resistance, and transaminases are scarce. We examined weight status, aspartate aminotransferase (AST), alanine aminotransferase (ALT), leptin, glucose, and insulin in 180 overweight children at baseline and 1 year later. Relationships between these parameters at baseline and their changes in the course of 1 year were determined by multiple regression analysis adjusted for age, sex, pubertal stage, and body mass index (BMI). Leptin but not homeostasis model assessment of insulin resistance index correlated significantly to transaminases in both cross-sectional and longitudinal analyses. The same findings were observed in 30 children with suspected nonalcoholic fatty liver disease by ultrasound. The 130 children who participated in a 1-year lifestyle intervention reduced their overweight (standard deviation score [SDS]-BMI, -0.37 +/- 0.11). In the course of 1 year, their changes of transaminases depended on change of weight status (SDS-BMI decrease >0.5: ALT 12 [10-15] --> 9 [8-13] U/L, AST 11 [9-12] --> 9 [8-12] U/L; SDS-BMI decrease >0 but <or=0.5: ALT 14 [11-18] --> 16 [12-26] U/L, AST 10 [8-14] --> 10 [8-24] U/L; no SDS-BMI decrease: ALT 13 [11-20] --> 20[13-33] U/L, AST 11 [9-21] --> 15 [9-24] U/L; data as median and interquartile range). The 50 children without intervention increased their SDS-BMI (+0.02 +/- 0.18) and transaminases (ALT 14 [11-18] --> 19 [15-25] U/L, AST 10 [8-15] --> 16 [10-25] U/L). These findings suggest that leptin may be involved in the pathogenesis of liver diseases. However, to test this hypothesis, careful histologic assessments in correlation to leptin levels are needed.
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PMID:Association between leptin and transaminases: 1-year follow-up study in 180 overweight children. 1930 70

Adipokines are polypeptides secreted in the adipose tissue in a regulated manner. While some of these molecules are expressed only by adipocytes, resident and infiltrating macrophages and components of the vascular stroma markedly contribute to expression of other adipokines. As a result, adipose tissue inflammation is associated with a modification in the pattern of adipokine secretion. Leptin, adiponectin, and resistin are the best-studied molecules in this class, but cytokines such as tumor necrosis factor or interleukin-6 are also secreted at high levels by the adipose tissue. Several other molecules have been recently identified and are actively investigated. Adipokines interfere with hepatic injury associated with fatty infiltration, differentially modulating steatosis, inflammation, and fibrosis. Several studies have investigated plasma levels of adiponectin in patients with nonalcoholic fatty liver disease, to establish correlations with the underlying state of insulin resistance and with the type and severity of hepatic damage. Hepatitis C is another disease where adipokines may represent a link between viral infection, steatosis, and metabolic disturbances. Identification of the mediators secreted by expanded adipose tissue and their pathogenic role is pivotal in consideration of the alarming increase in the prevalence of obesity and of the detrimental role that this condition exerts on the course of liver diseases.
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PMID:Adipokines in liver diseases. 1958 55


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