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)

This study explores the mechanisms responsible for the fatty liver setup in mice fed trans-10,cis-12 conjugated linoleic acid (t10c12 CLA), hypothesizing that an induction of low density lipoprotein receptor (LDLR) expression is associated with lipid accumulation. To this end, the effects of t10c12 CLA treatment on lipid parameters, serum lipoproteins, and expression of liver lipid receptors were measured in LDLR(-/-) apoB(100/100) mice as a model of human familial hypercholesterolemia itself depleted of LDLR. Mice were fed t10c12 CLA over 2 or 4 weeks. We first observed that the treatment induced liver steatosis, even in the absence of LDLR. Mice treated for 2 weeks exhibited hypertriglyceridemia with high levels of VLDL and HDL, whereas a 4 week treatment inversely induced a reduction of serum triglycerides (TGs), essentially through a decrease in VLDL levels. In the absence of LDLR, the mRNA levels of other proteins, such as VLDL receptor, lipoprotein lipase, and fatty acid translocase, usually not expressed in the liver, were upregulated, suggesting their involvement in the steatosis setup and lipoprotein clearance. The data also suggest that the TG-lowering effect induced by t10c12 CLA treatment was attributable to both the reduction of circulating free fatty acids in response to the severe lipoatrophy and the high capacity of liver to clear off plasma lipids.
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PMID:Upregulation of liver VLDL receptor and FAT/CD36 expression in LDLR-/- apoB100/100 mice fed trans-10,cis-12 conjugated linoleic acid. 1695 81

Obesity is increasing at an alarming rate, and its related disorders are placing a considerable strain on our healthcare system. Although they are not always coincident, obesity is often accompanied by hyperlipidemia. Both obesity and hyperlipidemia are independently associated with atherosclerosis, nonalcoholic fatty liver disease (NAFLD), and insulin resistance (IR). Thus, we sought to determine the relative contributions of obesity and hyperlipidemia to these associated pathologies. Obese agouti (A(y)/a) mice and their littermate controls (a/a) were placed on an LDL receptor (LDLR)(-/-) background. At 4 mo of age, mice were either maintained on chow diet (CD) or placed on Western diet (WD) for 12 wk. These genetic and dietary manipulations yielded four experimental groups: 1) lean, a/a;LDLR(-/-)CD; 2) genetic-induced obesity (GIO), A(y)/a;LDLR(-/-)CD; 3) diet-induced obesity (DIO), a/a;LDLR(-/-)WD; and 4) genetic- plus diet-induced obesity (GIO/DIO), A(y)/a;LDLR(-/-)WD. Lipoprotein profiles revealed increased VLDL and LDL particles in WD-fed mice compared with CD-fed controls. The hyperlipidemia present in this mouse model was the result of both increased hepatic triglyceride production and delayed lipoprotein clearance from the plasma. Both WD-fed groups exhibited similar levels of atherosclerotic lesion area, with increased obesity in the GIO/DIO group having no impact on atherogenesis. However, the severe obesity in the GIO/DIO group did aggravate NAFLD and IR. These findings suggest that, although obesity and hyperlipidemia exert individual pathological effects, the combination of the two has the potential to exert an additive effect on NAFLD and IR but not atherosclerosis in this mouse model.
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PMID:Obesity potentiates development of fatty liver and insulin resistance, but not atherosclerosis, in high-fat diet-fed agouti LDLR-deficient mice. 1756 16

Glucocorticoids, which are well established to regulate body fat mass distribution, adipocyte lipolysis, hepatic gluconeogenesis, and hepatocyte VLDL secretion, are speculated to play a role in the pathology of metabolic syndrome. Recent focus has been on the activity of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which is capable of regenerating, and thus amplifying, glucocorticoids in key metabolic tissues such as liver and adipose tissue. To determine the effects of global 11beta-HSD1 inhibition on metabolic syndrome risk factors, we subcutaneously injected "Western"-type diet-fed hyperlipidemic mice displaying moderate or severe obesity [LDL receptor (LDLR)-deficient (LDLR(-/-)) mice and mice derived from heterozygous agouti (A(y)/a) and homozygous LDLR(-/-) breeding pairs (A(y)/a;LDLR(-/-) mice)] with the nonselective 11beta-HSD inhibitor carbenoxolone for 4 wk. Body composition throughout the study, end-point fasting plasma, and extent of hepatic steatosis and atherosclerosis were assessed. This route of treatment led to detection of high levels of carbenoxolone in liver and fat and resulted in decreased weight gain due to reduced body fat mass in both mouse models. However, only A(y)/a;LDLR(-/-) mice showed an effect of 11beta-HSD1 inhibition on fasting insulin and plasma lipids, coincident with a reduction in VLDL due to mildly increased VLDL clearance and dramatically decreased hepatic triglyceride production. A(y)/a;LDLR(-/-) mice also showed a greater effect of the drug on reducing atherosclerotic lesion formation. These findings indicate that subcutaneous injection of an 11beta-HSD1 inhibitor allows for the targeting of the enzyme in not only liver, but also adipose tissue, and attenuates many metabolic syndrome risk factors, with more pronounced effects in cases of severe obesity and hyperlipidemia.
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PMID:Carbenoxolone treatment attenuates symptoms of metabolic syndrome and atherogenesis in obese, hyperlipidemic mice. 1787 20

To investigate the potential for pregnane X receptor (PXR) ligands as antiatherosclerotic drugs, we have determined the effect of PXR activation on lipid metabolism in an established atherosclerotic mouse model. LDL receptor knockout mice were treated with the PXR agonist PCN. PCN induced a striking 66% decrease in plasma LDL-cholesterol levels. PCN did not affect the cholesterol levels of high-density lipoprotein (HDL) or very-low-density lipoprotein (VLDL). VLDL-triglyceride levels were 2.2-fold increased by PCN, resulting in the presence of triglyceride-rich VLDL particles. This coincided with a 60% decreased hepatic lipase (HL)-mediated plasma lipolysis rate, which could be attributed to a decrease in the hepatic mRNA expression level of both HL (-31%) and its cofactor apolipoprotein A4 (-62%). In the liver, PCN induced a significant increase in the level of triglycerides (+65%) and phospholipids (+72%), a hallmark of hepatic steatosis, leading to a marked increase in Oil red O neutral lipid staining. A similar effect was noticed in ApoE knockout mice. Our studies show that activation of the nuclear receptor PXR by PCN leads to an inhibition of the plasma HL-mediated lipolysis rate, which is associated with a decrease in plasma LDL-cholesterol levels and induction of hepatic steatosis in LDL receptor knockout mice.
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PMID:Activation of the nuclear receptor PXR decreases plasma LDL-cholesterol levels and induces hepatic steatosis in LDL receptor knockout mice. 1918 6

We previously studied fatty acid metabolism in the liver of nonalcoholic fatty liver disease (NAFLD) and reported the activation of the LXRalpha-SREBP-1c pathway in hepatocytes. LXRalpha regulates cholesterol metabolism as well as fatty acid metabolism, and its agonistic ligands are oxysterols. Moreover, there is some evidence that excess cholesterol intake is involved in the onset of NAFLD. Therefore, in this study, we examined the expression of cholesterol metabolism-associated genes in the NAFLD liver by real-time PCR. Expression of LXRalpha and ACAT1 was up-regulated in NAFLD and this was more noticeable in non-obese rather than in obese patients. Although the expression of the LDL receptor, which acts on cholesterol uptake, and of SREBP-2, a positive key regulator of cholesterol, was suppressed, the expression of enzymes that promote cholesterol synthesis was uniformly increased in NAFLD. Gene expression of apoB100 and microsomal triglyceride transfer protein, which are associated with VLDL secretion, and ABCG5, which is involved in cholesterol excretion, was significantly elevated in NAFLD. Because cholesterol accumulates in hepatocytes in NAFLD liver, cholesterol uptake and synthesis should be physiologically down-regulated. However, cholesterol synthesis was activated in NAFLD liver, meaning that cholesterol metabolism is dysregulated in NAFLD. Overproduction of cholesterol may lead to an increased level of oxysterols, activation of LXRalpha and SREBP-1c, and enhanced fatty acid synthesis.
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PMID:Impact of cholesterol metabolism and the LXRalpha-SREBP-1c pathway on nonalcoholic fatty liver disease. 1936 Mar 18

Obesity is often associated with dyslipidemia, insulin resistance, and hypertension. Together, these metabolic perturbations greatly increase the risk of developing cardiovascular disease and diabetes. Although fish oil is a well-established hypolipidemic agent, the mechanisms by which it mediates its lipid-lowering effects are not clear. In addition, it has not been established whether dietary fish oil has different effects in lean and obese mice. LDL receptor deficient (LDLR-/-) and leptin deficient mice on a LDLR-/- background (ob/ob;LDLR-/-) were fed a high fat diet (39% total fat) supplemented with 6% olive oil or fish oil for 6 wk. Fish oil supplementation resulted in lower concentrations of plasma total cholesterol (P < 0.01), triglycerides (P < 0.01), and free fatty acids (P < 0.001) in lean LDLR-/- mice, but not in ob/ob;LDLR-/- mice. In contrast, a fish oil diet did not modulate insulin sensitivity in lean LDLR-/- mice, but it improved insulin sensitivity in ob/ob;LDLR-/- mice (P < 0.05) compared with olive oil fed ob/ob;LDLR-/- mice. Interestingly, plasma adiponectin concentrations were significantly higher and hepatic steatosis was reduced in both mouse models upon fish oil feeding. Finally, fish oil fed LDLR-/- mice exhibited higher hepatic AMP activated protein kinase (AMPK) phosphorylation (P < 0.05), whereas AMPK phosphorylation was not elevated by fish oil feeding in ob/ob;LDLR-/- mice. Taken together, our data suggest that fish oil reduces hepatic steatosis in both lean and obese mice, has potent plasma lipid lowering effects in lean mice, and exerts insulin sensitizing effects in obese mice.
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PMID:Dietary fish oil exerts hypolipidemic effects in lean and insulin sensitizing effects in obese LDLR-/- mice. 1986 3

To investigate the impact of mipomersen, an apolipoprotein B-100 (apoB) synthesis inhibitor, on intra-hepatic triglyceride content (IHTG content), we conducted a randomized, double-blind, placebo-controlled study in 21 patients with familial hypercholesterolemia (FH). Subjects received a weekly subcutaneous dose of 200 mg mipomersen or placebo for 13 weeks while continuing conventional lipid lowering therapy. The primary endpoint was change in IHTG content from week 0 to week 15 as measured by localized proton magnetic resonance spectroscopy (1H-MRS). Thirteen weeks of mipomersen administration reduced LDL-cholesterol by 22.0 (17.8) % and apoB by 19.9 (17.4) % (both P < 0.01). One of 10 patients (10%) in the mipomersen-treated group developed mild hepatic steatosis at week 15, which was reversible following mipomersen discontinuation. For the group, there was a trend toward an increase in IHTG content [placebo; baseline: 1.2% and week 15: 1.1%; change -0.1 (0.9). Mipomersen; baseline: 1.2% and week 15: 2.1%; change 0.8 (1.7) (P = 0.0513)]. Mipomersen administration for 13 weeks to subjects with FH is associated with a trend toward an increase in IHTG content. Future studies evaluating the effects of long-term use of mipomersen reaching more profound reductions in apoB are required prior to broader use of this compound.
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PMID:Effect of apolipoprotein-B synthesis inhibition on liver triglyceride content in patients with familial hypercholesterolemia. 2004 43

We investigated the effects of dietary trans fatty acids, PUFA, and SFA on body and liver fat content, liver histology, and mRNA of enzymes involved in fatty acid metabolism. LDL receptor knockout weaning male mice were fed for 16 wk with diets containing 40% energy as either trans fatty acids (TRANS), PUFA, or SFA. Afterwards, subcutaneous and epididymal fat were weighed and histological markers of nonalcoholic fatty liver disease (NAFLD) were assessed according to the Histological Scoring System for NAFLD. PPARalpha, PPARgamma, microsomal triglyceride transfer protein (MTP), carnitine palmitoyl transferase 1 (CPT-1), and sterol regulatory element binding protein-1c (SREBP-1c) mRNA were measured by quantitative RT-PCR. Food intake was similar in the 3 groups, although mice fed the TRANS diet gained less weight than those receiving the PUFA diet. Compared with the PUFA- and SFA-fed mice, TRANS-fed mice had greater plasma total cholesterol (TC) and triglyceride (TG) concentrations, less epididymal and subcutaneous fat, larger livers with nonalcoholic steatohepatitis (NASH)-like lesions, and greater liver TC and TG concentrations. Macrosteatosis in TRANS-fed mice was associated with a higher homeostasis model assessment of insulin resistance (HOMA(IR)) index and upregulated mRNA related to hepatic fatty acid synthesis (SREBP-1c and PPARgamma) and to downregulated MTP mRNA. Diet consumption did not alter hepatic mRNA related to fatty acid oxidation (PPARalpha and CPT-1). In conclusion, compared with PUFA- and SFA-fed mice, TRANS-fed mice had less adiposity, impaired glucose tolerance characterized by greater HOMA(IR) index, and NASH-like lesions due to greater hepatic lipogenesis. These results demonstrate the role of trans fatty acid intake on the development of key features of metabolic syndrome.
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PMID:Intake of trans fatty acids causes nonalcoholic steatohepatitis and reduces adipose tissue fat content. 2035 81

Microsomal triglyceride transfer protein (MTP) is involved in the synthesis of very low density lipoprotein in the liver. Its deficiency results in abetalipoproteinemia. MTP inhibitors target the assembly and secretion of apolipoprotein B-containing lipoproteins. These agents may potentially play a role, alone or in combination, in the treatment of hypercholesterolemia or hypertriglyceridaemia. Clinical applications of MTP inhibitors initially focused primarily on high-dose monotherapy in order to produce substantial reductions in LDL-cholesterol levels but these proved to induce significant hepatic steatosis and transaminase elevations. However, likely orphan indications for MTP inhibitors, where a different risk-benefit profile applies, include patients with homozygous familial hypercholesterolemia where statins often show a low response. Development of MTP inhibitors has continued to enter clinical trials at lower doses or in formulations aimed at utilizing their efficacy while avoiding their side effects. These have shown promising results in reducing cholesterol, triglycerides and apolipoprotein B with a far lower incidence of, often, transient side-effects. The clinical efficacy and safety of MTP inhibition in patients with hyperlipidaemia remains to be fully determined and to be proven in both surrogate and clinical endpoint trials but there may be a role for these agents in orphan indications for rarer severe hyperlipidaemias.
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PMID:New lipid modulating drugs: the role of microsomal transport protein inhibitors. 2141 29

AMPK has emerged as a critical mechanism for salutary effects of polyphenols on lipid metabolic disorders in type 1 and type 2 diabetes. Here we demonstrate that AMPK interacts with and directly phosphorylates sterol regulatory element binding proteins (SREBP-1c and -2). Ser372 phosphorylation of SREBP-1c by AMPK is necessary for inhibition of proteolytic processing and transcriptional activity of SREBP-1c in response to polyphenols and metformin. AMPK stimulates Ser372 phosphorylation, suppresses SREBP-1c cleavage and nuclear translocation, and represses SREBP-1c target gene expression in hepatocytes exposed to high glucose, leading to reduced lipogenesis and lipid accumulation. Hepatic activation of AMPK by the synthetic polyphenol S17834 protects against hepatic steatosis, hyperlipidemia, and accelerated atherosclerosis in diet-induced insulin-resistant LDL receptor-deficient mice in part through phosphorylation of SREBP-1c Ser372 and suppression of SREBP-1c- and -2-dependent lipogenesis. AMPK-dependent phosphorylation of SREBP may offer therapeutic strategies to combat insulin resistance, dyslipidemia, and atherosclerosis.
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PMID:AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. 2145 23


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