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)

Nonalcoholic steatohepatitis (NASH) and alcoholic steatohepatitis (ASH) and typically are indistinguishable, histologically. The diagnosis relies on reporting of alcohol consumption. The metabolic syndrome involving insulin resistance is associated with nonalcoholic fatty liver disease (NAFLD). Protein tyrosine phosphatase 1B (PTP1B) negatively regulates the insulin receptor (IR). Increased PTP1B expression is seen in obesity and possibly is responsible for the insulin resistance seen in the metabolic syndrome. The study objective was to determine whether biopsy specimens with steatohepatitis could be classified accurately as alcoholic or nonalcoholic by immunohistochemical stains. We selected 241 cases of steatohepatitis, comprising 53 and 188 cases of alcoholic and NAFLD, respectively. Specimens were stained with PTP1B and IR (b subunit) and classified as NASH or ASH. The staining pattern predicted 60 cases of ASH and 181 cases of NASH. Results correlated with clinical diagnoses in 70% and 88% of ASH and NASH cases, respectively (odds ratio, 16.6; 95% confidence interval, 8.2-35.4).
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PMID:The use of protein tyrosine phosphatase 1B and insulin receptor immunostains to differentiate nonalcoholic from alcoholic steatohepatitis in liver biopsy specimens. 1574 53

Non-alcoholic steatohepatitis is a chronic disease that occurs in persons without significative consumption of alcohol, characterized by macrovesicular steatosis, mixed inflammatory infiltrate, and diverse degrees of fibrosis. It can progress to cirrhosis and its evolution to hepatocellular carcinoma has been described. It principally occurs in patients with obesity, diabetes mellitus, and hyperlipidemia, and is at present considered a manifestation of metabolic syndrome with insulin resistance. In pathogenesis, diverse factors, fundamentally insulin resistance as a mechanism that determines hepatic steatosis, have been described. Later, alteration of signalling cascades, oxidative stress, and other mechanisms occur that lead to inflammation, necrosis, and finally to hepatic fibrosis, the details of which will be described in this review.
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PMID:[Pathogenic molecular mechanisms in non-alcoholic steatohepatitis]. 1575 91

Nonalcoholic fatty liver disease is emerging as the most common chronic liver condition in the Western world. It is associated with insulin resistance and frequently occurs with features of the metabolic syndrome. Disease presentation ranges from asymptomatic elevated liver enzyme levels to cirrhosis with complications of liver failure and hepatocellular carcinoma. Current treatment recommendations are limited to weight loss and exercise, although several promising medications are on the horizon. In this article we discuss the etiology, pathogenesis and diagnosis of nonalcoholic fatty liver disease as well as approaches to its management.
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PMID:Nonalcoholic fatty liver disease. 1618 72

Plasma levels of adiponectin are decreased in patients with nonalcoholic fatty liver disease (NAFLD), but the relationship among plasma adiponectin, insulin sensitivity, and histological features is unclear. In 174 NAFLD patients and 42 controls, we examined plasma adiponectin concentrations in relation to 1) lipid profile, indices of insulin resistance, and features of the metabolic syndrome (n = 174); 2) hepatic insulin resistance (clamp technique with tracer infusion) (10 patients); and 3) histological features at liver biopsy (n = 116). When the data from all subjects were combined, plasma adiponectin levels were positively associated with increased age, female gender, and plasma high-density lipoprotein levels, and negatively associated with waist circumference, body mass index, triglycerides, indices of insulin resistance, and aminotransferase levels, and also predicted the presence of the metabolic syndrome. In step-wise regression, increased age, female gender, waist circumference, triglyceride levels, and homeostasis model assessment independently associated with adiponectin (adjusted R(2), 0.329). In NAFLD, adiponectin was only associated with increased age, female gender, and triglycerides (adjusted R(2), 0.245). When the measured histological parameters were included in the model, plasma adiponectin levels were also inversely proportional to the percentage of hepatic fat content (adjusted R(2), 0.221), whereas necroinflammation and fibrosis did not fit in the model. Adiponectin was negatively correlated with insulin-suppressed endogenous glucose production during the clamp (P = 0.011). The results demonstrate that decreased levels of circulating adiponectin in NAFLD are related to hepatic insulin sensitivity and to the amount of hepatic fat content. Hypoadiponectinemia in NAFLD is part of a metabolic disturbance characterized by ectopic fat accumulation in the central compartment.
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PMID:Plasma adiponectin in nonalcoholic fatty liver is related to hepatic insulin resistance and hepatic fat content, not to liver disease severity. 1579 48

Fatty liver is extremely common in insulin-resistant patients with either obesity or lipodystrophy and it has been proposed that hepatic steatosis be considered an additional feature of the metabolic syndrome. Although insulin resistance can promote fatty liver, excessive hepatic accumulation of fat can also promote insulin resistance and could contribute to the pathogenesis of the metabolic syndrome. We sought to create a new nonobese rat model with hypertension, hepatic steatosis, and the metabolic syndrome by transgenic overexpression of a sterol-regulatory element-binding protein (SREBP-1a) in the spontaneously hypertensive rat (SHR). SREBPs are transcription factors that activate the expression of multiple genes involved in the hepatic synthesis of cholesterol, triglycerides, and fatty acids. The new transgenic strain of SHR overexpressing a dominant-positive form of human SREBP-1a under control of the phosphoenolpyruvate carboxykinase (PEPCK) promoter exhibited marked hepatic steatosis with major biochemical features of the metabolic syndrome, including hyperglycemia, hyperinsulinemia, and hypertriglyceridemia. Both oxidative and nonoxidative skeletal muscle glucose metabolism were significantly impaired in the SHR transgenic strain and glucose tolerance deteriorated as the animals aged. The SHR transgenic strain also exhibited reduced body weight and reduced adipose tissue stores; however, the level of hypertension in the transgenic SHR was similar to that in the nontransgenic SHR control. The transgenic SHR overexpressing SREBP-1a represents a nonobese rat model of fatty liver, disordered glucose and lipid metabolism, and hypertension that may provide new opportunities for studying the pathogenesis and treatment of the metabolic syndrome associated with hepatic steatosis.
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PMID:A new transgenic rat model of hepatic steatosis and the metabolic syndrome. 1580 59

The most known risk factor for nonalcoholic fatty liver disease (NAFLD) is the metabolic syndrome. In this study, we characterized changes in liver pathology, hepatic lipid composition, and hepatic iron concentration (HIC) occurring in rats given fructose-enriched diet (FED), with and without therapeutic maneuvers to reduce blood pressure and plasma triglycerides. Rats were given FED or standard rat chow for 5 weeks. Rats on FED were divided into 4 groups: receiving amlodipine (15 mg/kg per day), captopril (90 mg/kg per day), bezafibrate (10 mg/kg per day) in the last 2 weeks, or a control group that received FED only. FED rats had hepatic macrovesicular and microvesicular fat deposits develop, with increase in hepatic triglycerides (+198%) and hepatic cholesterol (+89%), but a decrease in hepatic phospholipids (-36%), hypertriglyceridemia (+223%), and hypertension (+15%), without increase in HIC. Amlodipine reduced blood pressure (-18%), plasma triglycerides (-12%), but there was no change in hepatic triglycerides and phospholipids concentrations. Captopril reduced blood pressure (-24%), plasma triglycerides (-36%), hepatic triglycerides (-51%), and hepatic macrovesicular fat (-51%), but increased HIC (+23%), with a borderline increase in hepatic fibrosis. Bezafibrate reduced plasma triglycerides (-49%), hepatic triglycerides (-78%), hepatic macrovesicular fat (-90%), and blood pressure (-11%). We conclude that FED rats can be a suitable model for human NAFLD. Drugs administered to treat various aspects of the metabolic syndrome could have hepatic effects. An increase in HIC in rats with NAFLD could be associated with increased hepatic fibrosis.
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PMID:Fructose-induced fatty liver disease: hepatic effects of blood pressure and plasma triglyceride reduction. 1582 94

Pathogenic role of intrahepatic lipid accumulation in insulin resistance and metabolic syndrome has been well documented. Liver steatosis constitutes a risk factor for nonalcoholic steatohepatitis (NASH), one of the leading causes of obesity-related morbidity and mortality. Although pathophysiology of steatosis is multifactorial, a line of evidence from rodent studies suggests that PPARalpha and PPARgamma are involved. PPARalpha is highly expressed in liver and its activation by agonists leads to augmented fatty acid oxidation and protects against steatosis. PPARgamma, which is transcriptionally up-regulated in steatosis, activates lipogenic enzymes and exacerbates steatosis. However, recent human studies have suggested that PPARgamma agonists improve NASH possibly by its primary insulin-sensitizing effect on adipocytes. PPARs modulation is becoming a rational and effective therapeutic approach for the treatment of nonalcoholic fatty liver disease.
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PMID:[Role of PPARs in the pathophysiology of nonalcoholoic fatty liver disease]. 1582 40

Stearoyl-CoA desaturase (SCD), the rate-limiting enzyme in monounsaturated fatty acid synthesis, has recently been shown to be the critical control point regulating hepatic lipogenesis and lipid oxidation. As several manifestations of the metabolic syndrome and type 2 diabetes mellitus are associated with alterations in intracellular lipid partitioning, we propose that SCD1 may be a potential therapeutic target in the treatment of obesity and the metabolic syndrome. In support of this notion, we have shown that SCD1-deficient mice have increased energy expenditure, reduced body adiposity, increased insulin sensitivity and are resistant to diet-induced obesity and liver steatosis. Furthermore, SCD1 was found to be specifically repressed during leptin-mediated weight loss, and leptin-deficient ob/ob mice lacking SCD1 showed marked correction of the hypometabolic phenotype and hepatic steatosis. Much evidence indicates that the direct anti-steatotic effect of SCD1 deficiency stems from increased fatty acid oxidation and decreased lipid synthesis. All of these findings reveal that pharmacological manipulation of SCD activity might be of benefit in the treatment of obesity, diabetes, liver steatosis and other diseases of the metabolic syndrome.
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PMID:Stearoyl-CoA desaturase as a new drug target for obesity treatment. 1583 67

The CLOCK transcription factor is a key component of the molecular circadian clock within pacemaker neurons of the hypothalamic suprachiasmatic nucleus. We found that homozygous Clock mutant mice have a greatly attenuated diurnal feeding rhythm, are hyperphagic and obese, and develop a metabolic syndrome of hyperleptinemia, hyperlipidemia, hepatic steatosis, hyperglycemia, and hypoinsulinemia. Expression of transcripts encoding selected hypothalamic peptides associated with energy balance was attenuated in the Clock mutant mice. These results suggest that the circadian clock gene network plays an important role in mammalian energy balance.
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PMID:Obesity and metabolic syndrome in circadian Clock mutant mice. 1584 77

Both environmental and genetic factors play important roles in the development of the metabolic syndrome. To elucidate how these factors interact under normal conditions, C57Bl/6 (B6) and 129S6/SvEvTac (129) mice were placed on a low-fat or high-fat diet. Over 18 weeks, the 129 strain developed features of the metabolic syndrome, notably obesity, hyperinsulinemia, and glucose intolerance only on the high-fat diet; the B6 strain on the other hand developed these features on both diets. High-fat feeding of both strains led to decreased serum triglycerides, hepatic steatosis, and hypercholesterolemia; however, B6 mice developed worse steatosis and a larger increase in LDL cholesterol. Both B6 background and high-fat feeding increased sterol regulatory element-binding protein-1c (SREBP-1c), a key regulator of lipogenic gene transcription, and its downstream targets. Stearoyl-CoA desaturase 1 (SCD1), an enzyme that regulates monounsaturated fatty acid (MUFA) synthesis, was also increased at the mRNA and enzyme activity levels by both high-fat feeding and B6 background. Furthermore, lipid analysis revealed increased hepatic triglycerides and MUFAs in B6 and high-fat-fed mice. Thus, dietary fat and genetic background act through SREBP-1c and SCD1 to affect hepatic lipid metabolism contributing to the development of the metabolic syndrome.
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PMID:Effects of diet and genetic background on sterol regulatory element-binding protein-1c, stearoyl-CoA desaturase 1, and the development of the metabolic syndrome. 1585 15


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