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)

Lysosomal acid lipase (LAL) deficiency results in Wolman disease and cholesteryl ester storage disease (CESD), a more benign form. CESD is a recessive disorder characterized by hypercholesterolaemia, hypertriglyceridaemia, low blood HDL and variable phenotype, while hepatomegaly is usually evident during childhood or adolescence. An 11-year-old girl was referred to our department for combined hyperlipidaemia (total cholesterol 323, triglycerides 259 mg/dl). All family members had normal lipid profile and liver function tests. At 8 years she was admitted for acute Epstein-Barr virus infection, with hepatosplenomegaly and elevation of liver enzymes. Liver-spleen enlargement resolved, but serum alanine aminotransferase and aspartate aminotransferase were persistently twice the upper limits, with other liver function tests within the normal range. Ultrasonography showed normal liver and spleen size and minimal hepatic steatosis. Infectious, autoimmune and metabolic causes of elevated liver enzymes were ruled out, including glycogen storage disease. Dysbetalipoproteinaemia was also ruled out (ApoE phenotype: E3E3). In the following 2 years the girl was symptom-free, BMI was at the 50th-75th centile for age and lipid profile was unchanged despite a low-fat diet. At 13 years of age, low acid lipase activity was demonstrated in leukocytes (10 nmol/h/ per mg protein, normal 140-380) and cultured skin fibroblasts (181 nmol/h per mg protein, normal 1100-2400), leading to diagnosis of CESD. CESD usually progresses to hepatic fibrosis, with high risk of premature atherosclerosis. CESD prevalence may be underestimated in the general population. The diagnosis may be considered in all subjects with atypical combined hyperlipidaemia (usually dominant in transmission or related to metabolic syndrome) and atypical 'fatty liver disease', in the absence of overweight.
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PMID:Combined hyperlipidaemia as a presenting sign of cholesteryl ester storage disease. 1921 73

The World Health Organization estimates that since 1980 the prevalence of obesity has increased more than threefold throughout much of the world, and this increase is not limited to developed nations. Indeed, the incidence of obesity is increasing most rapidly among rapidly industrializing countries raising the spectre of a burgeoning epidemic in obesity-associated diseases, including diabetes, dyslipidemia, nonalcoholic fatty liver disease and atherosclerosis. Reducing the rates of obesity and its attendant complications will require both coordinated public health policy and a better understanding of the pathophysiology of obesity. Obesity is associated with low grade chronic inflammation, a common feature of many complications of obesity that appears to emanate in part from adipose tissue. In obese individuals and rodents adipose tissue macrophage accumulation is a critical component in the development of obesity-induced inflammation. The macrophages in adipose tissue are bone marrow-derived and their number is strongly correlated with bodyweight, body mass index and total body fat. The recruited macrophages in adipose tissue express high levels of inflammatory factors that contribute to systemic inflammation and insulin resistance. Interventions aimed at either reducing macrophage numbers or decreasing their inflammatory characteristics improves insulin sensitivity and decreases inflammation. Macrophage accumulation and adipose tissue inflammation are dynamic processes under the control of multiple mechanisms. Investigating the role of macrophages in adipose tissue biology and the mechanisms involved in their recruitment and activation in obesity will provide useful insights for developing therapeutic approaches to treating obesity-induced complications.
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PMID:Obesity, inflammation, and macrophages. 1934 74

Hepatic metabolic derangements are key components in the development of fatty liver, insulin resistance, and atherosclerosis. SIRT1, a NAD+-dependent protein deacetylase, is an important regulator of energy homeostasis in response to nutrient availability. Here we demonstrate that hepatic SIRT1 regulates lipid homeostasis by positively regulating peroxisome proliferators-activated receptor alpha (PPARalpha), a nuclear receptor that mediates the adaptive response to fasting and starvation. Hepatocyte-specific deletion of SIRT1 impairs PPARalpha signaling and decreases fatty acid beta-oxidation, whereas overexpression of SIRT1 induces the expression of PPARalpha targets. SIRT1 interacts with PPARalpha and is required to activate PPARalpha coactivator PGC-1alpha. When challenged with a high-fat diet, liver-specific SIRT1 knockout mice develop hepatic steatosis, hepatic inflammation, and endoplasmic reticulum stress. Taken together, our data indicate that SIRT1 plays a vital role in the regulation of hepatic lipid homeostasis and that pharmacological activation of SIRT1 may be important for the prevention of obesity-associated metabolic diseases.
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PMID:Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. 1935 14

Endocannabinoids are endogenous bioactive lipid mediators present both in the brain and various peripheral tissues, which exert their biological effects via interaction with specific G-protein-coupled cannabinoid receptors, the CB(1) and CB(2). Pathological overactivation of the endocannabinoid system (ECS) in various forms of shock and heart failure may contribute to the underlying pathology and cardiodepressive state by the activation of the cardiovascular CB(1) receptors. Furthermore, tonic activation of CB(1) receptors by endocannabinoids has also been implicated in the development of various cardiovascular risk factors in obesity/metabolic syndrome and diabetes, such as plasma lipid alterations, abdominal obesity, hepatic steatosis, inflammation, and insulin and leptin resistance. In contrast, activation of CB(2) receptors in immune cells exerts various immunomodulatory effects, and the CB(2) receptors in endothelial and inflammatory cells appear to limit the endothelial inflammatory response, chemotaxis, and inflammatory cell adhesion and activation in atherosclerosis and reperfusion injury. Here, we will overview the cardiovascular actions of endocannabinoids and the growing body of evidence implicating the dysregulation of the ECS in a variety of cardiovascular diseases. We will also discuss the therapeutic potential of the modulation of the ECS by selective agonists/antagonists in various cardiovascular disorders associated with inflammation and tissue injury, ranging from myocardial infarction and heart failure to atherosclerosis and cardiometabolic disorders.
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PMID:The emerging role of the endocannabinoid system in cardiovascular disease. 1935 46

The incidence of obesity has increased dramatically during recent decades. Obesity will cause a decline in life expectancy for the first time in recent history due to numerous co-morbid disorders. Adipocyte and adipose tissue dysfunction belong to the primary defects in obesity and may link obesity to several health problems including increased risk of insulin resistance, type 2 diabetes, fatty liver disease, hypertension, dyslipidemia, atherosclerosis, dementia, airway disease and some cancers. However, not all obese individuals develop obesity related metabolic or cardiovascular disorders potentially due to a preserved normal adipose tissue architecture and function. The majority of patients with obesity have an impaired adipose tissue function caused by the interaction of genetic and environmental factors which lead to adipocyte hypertrophy, hypoxia, a variety of stresses and inflammatory processes within adipose tissue. Ectopic fat accumulation including visceral obesity may be considered as a consequence of adipose tissue dysfunction, which is further characterized by changes in the cellular composition, increased lipid storage and impaired insulin sensitivity in adipocytes, and secretion of a proinflammatory, atherogenic, and diabetogenic adipokine pattern. This review focuses on the discussion of mechanisms causing or maintaining impaired adipose tissue function in obesity and potentially linking obesity to its associated disorders. A model is proposed how different pathogenic factors and mechanisms may cause dysfunction of adipose tissue.
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PMID:Adipose tissue dysfunction in obesity. 1935 89

The liver plays a central role in whole-body lipid metabolism by governing the synthesis, oxidization, transport and excretion of lipids. The unfolded protein response (UPR) was identified as a signal transduction system that is activated by ER stress. Recent studies revealed a critical role of the UPR in hepatic lipid metabolism. The IRE1/XBP1 branch of the UPR is activated by high dietary carbohydrates and controls the expression of genes involved in fatty acid and cholesterol biosynthesis. PERK mediated eIF2alpha phosphorylation is also required for the expression of lipogenic genes and the development of hepatic steatosis, likely by activating C/EBP and PPARgamma transcription factors. Further studies to define the molecular pathways that lead to the activation of the UPR by nutritional cues in the liver, and their contribution to human metabolic disorders such as hepatic steatosis, atherosclerosis and type 2 diabetes that are associated with dysregulation of lipid homeostasis, are warranted.
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PMID:Intersection of the unfolded protein response and hepatic lipid metabolism. 1946 85

Atherosclerosis is a leading cause of morbidity and mortality worldwide. Statins are established as first choice drugs for the management of hyperlipidaemia and cardiovascular risk. However, a residual cardiovascular risk, partially attributable to lipids, remains even after statin treatment. This risk appears to be associated with both high-density lipoprotein cholesterol and triglyceride lipid fractions. Several novel therapeutic approaches have been proposed to reduce lipid levels. Microsomal transfer protein (MTP) is involved in the assembly of very-low-density lipoprotein and chylomicron lipoprotein particles in the liver and the gut, respectively. In the preclinical setting, various agents that affect activity of MTP have shown that inhibition can result in profound reductions in blood triglycerides and cholesterol. Similarly, evidence of efficacy using the target has been confirmed in man with small molecule inhibitors and antisense oligonucleotides. Unfortunately, despite their efficacy in reducing lipids, the clinical utility of small molecule inhibitors has been restricted by their potential to induce hepatic steatosis. Continuing attempts to utilise this clinical target (to decrease cholesterol, triglycerides and weight) have involved the use of lower doses or non systemically absorbed MTP inhibitors.
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PMID:Future challenges for microsomal transport protein inhibitors. 2070 Sep 2

Lipogenesis occurs primarily in the liver, where dietary carbohydrates control the expression of key enzymes in glycolytic and lipogenic pathways. We have recently discovered that the transcription factor XBP1, best known as a key regulator of the unfolded protein response (UPR), is required for de novo fatty acid synthesis in the liver, a function unrelated to its role in the UPR.(1) XBP1 protein expression is induced in the liver by a high carbohydrate diet and directly controls the induction of critical genes involved in fatty acid synthesis. Specific deletion of XBP1 in adult liver using an inducible approach results in profound hypocholesterolemia and hypotriglyceridemia, which could be attributed to diminished production of lipids in the liver. Notably, this phenotype is not associated with fatty liver (hepatic steatosis) or significant compromise in protein secretion. XBP1 joins an already rich field of transcriptional regulatory proteins in the control of hepatic lipogenesis. Its function in lipogenesis appears to be highly significant as evidenced by the phenotype of the genetic mutant strain. A more complete understanding of the mechanisms by which XBP1 accelerates de novo fatty acid synthesis in the liver while preserving normal hepatic lipid composition is highly relevant to the treatment of diseases such as atherosclerosis and metabolic syndrome that are associated with dyslipidemia. Since excess fat accumulation in the liver could result from increased hepatic fatty acid synthesis, compounds that inhibit XBP1 activation may also be useful therapeutics for the treatment of human alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD), increasingly common causes of morbidity and mortality in the United States.
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PMID:From sugar to fat: How the transcription factor XBP1 regulates hepatic lipogenesis. 1975 10

Cholesterol and sphingolipids are major lipid constituents of the plasma membrane and have been implicated in a number of human diseases, such as atherosclerosis, fatty liver, diabetes mellitus, coronary heart disease, and hypertension. However, the relationship between cholesterol and sphingolipid metabolism has not been investigated. The purpose of this study was to determine whether dietary cholesterol would induce the alteration of sphingolipid metabolism in hamsters. Hypercholesterolemia was induced in hamsters by placing them on an experimental diet containing 0.5% cholesterol plus 0.5% choline chloride for 8 and 12 weeks. The serum profile of the hamsters showed that the administration of cholesterol increased the levels of total cholesterol, LDL cholesterol, and triglycerides as well as the activities of GOT and GPT. The levels of ceramide and sphingosine-1-phosphate (So-1-P) were remarkably elevated by 6-fold, respectively, in the bile juice of cholesterol-fed hamsters. Interestingly, the levels of iNOS and GFAP were increased in the gallbladders of cholesterol-fed hamsters. In addition, the immunostaining of pSTAT3 was increased on the gallbladder epithelium after cholesterol feeding. These results suggest that sphingolipid metabolism may be regulated in the bile juice during cholesterol feeding and may be a potential target for the treatment of hypercholesterolemia-induced diseases.
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PMID:Alteration of sphingolipid metabolism and pSTAT3 expression by dietary cholesterol in the gallbladder of hamsters. 1978 70

Young adults with abdominal obesity are liable to have subclinical atherosclerosis that may contribute to an increased risk of cardiovascular disease later in life. This study aims to evaluate subclinical atherosclerosis and its possible correlation with some inflammatory and biochemical markers in Egyptian young adult males with abdominal obesity. The study includes 50 young adult males (age range: 19-29 years) divided into two groups. Group 1 comprises 20 non-obese subjects (controls). Group 2 comprises 30 apparently healthy obese subjects. Carotid intima media thickness (carotid-IMT) was estimated using B-mode ultrasonography of the common carotid arteries, and abdominal ultrasonography was performed to assess the presence of a fatty liver. Laboratory investigations included fasting levels of serum glucose, triglycerides (TG), cholesterol (total [TC], high-density [HDL-cholesterol] and low-density [LDL-cholesterol] lipoprotein fractions), high-sensitivity C-reactive protein (hs-CRP), neopterin, lipoprotein-a (Lp[a]), gamma glutamyl transferase (GGT), aspartate and alanine aminotransferases (AST, ALT), plasma plasminogen and fibrinogen. Results showed that carotid IMT, serum hs-CRP, neopterin, Lp(a), fibrinogen, plasminogen, TC, TG, LDL-cholesterol and liver enzymes were significantly elevated (P<0.001) in the obese group compared to controls. All obese subjects showed evidence of fatty liver. A significant positive correlation was found between carotid-IMT and body mass index, waist circumference, waist/hip ratio, cholesterol, triglycerides, neopterin, hs-CRP AST, ALT and GGT. Elevated serum levels of inflammatory biomarkers and increased ALT, AST and GGT, and non-alcoholic fatty liver disease biomarkers may be useful predictors of subclinical atherosclerosis.
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PMID:Evaluation of some markers of subclinical atherosclerosis in Egyptian young adult males with abdominal obesity. 1983 25


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