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)

The effects of fasting on hepatic lipid metabolism in mice fed a high-fat diet (HFD) are still unclear. After fasting, the degree of hepatic lipid accumulation differs between HFD-fed C57BL/6J (B6) and BALB/cA (BALB/c) mice. It is not clear whether this difference is due to sensitivity to fasting or HFD. The aim of this study is to elucidate this difference among strains. After nine weeks of HFD feeding, both B6 and BALB/c mice showed moderate hepatic steatosis. However, after a subsequent twenty-hour fast, the hepatic lipid accumulation was markedly decreased in B6 but not in BALB/c mice. Moreover, the mRNA expression of a transcription factor, Srebp1(regulates hepatic lipid metabolism), and its target genes-malic enzyme, acetyl-CoA carboxylase, fatty acid synthase(regulate fatty acid synthesis), and glycerol-3-phosphate acyltransferase(regulates triacylglycerol synthesis)-were more markedly reduced in B6 than BALB/c mice. In conclusion, fasting may modify hepatic lipid accumulation in HFD-fed B6 and BALB/c mice differently. The difference may be partly owing to a marked downregulation of the expression of some lipid-metabolism-related genes in B6 mice. These results suggest that fasting per se has a significant effect on hepatic lipid accumulation in mouse strains. SREBP1 might play a role in this fasting effect.
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PMID:The effect of fasting on hepatic lipid accumulation and transcriptional regulation of lipid metabolism differs between C57BL/6J and BALB/cA mice fed a high-fat diet. 1881 81

We have previously established a correlation between reduced mitochondrial glycerol-3-phosphate acyltransferase-1 (GPAT-1) activity and decreased proliferation in splenic T-lymphocytes from aged rats. To better understand the immunoregulatory role of GPAT-1, we examined T-lymphocyte function in young GPAT-1 knockout (KO) mice. We show that without GPAT-1, T-lymphocyte proliferation is inhibited and activation induced apoptosis is increased. Th-1 (IL-2 and IFN-gamma) cytokine secretion is reduced, and Th-2 (IL-4 and IL-10) cytokine secretion is increased. These changes may be due to alterations in membrane lipid composition since we found changes in the relative content of individual phospholipid species. Furthermore, we show increased arachidonate content and subsequent increased prostaglandin E(2) secretion, which may inhibit T-lymphocyte proliferation. Taken together, we show a novel link between GPAT-1 and changes in T-lymphocyte function. These data have broad health implications because GPAT-1 suppression has recently been implicated as a new target for preventing insulin sensitivity and hepatic steatosis and we show that immune function may also be affected. Interestingly, the changes in young GPAT-1 KO splenic T-lymphocytes are similar to defects commonly seen in T-lymphocytes from aged rodents, which further underscores the significance of GPAT-1 in T-lymphocyte function.
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PMID:Glycerol-3-phosphate acyltransferase-1 regulates murine T-lymphocyte proliferation and cytokine production. 1897 90

Maternal obesity is thought to increase the offspring's risk of juvenile obesity and metabolic diseases; however, the mechanism(s) whereby excess maternal nutrition affects fetal development remain poorly understood. Here, we investigated in nonhuman primates the effect of chronic high-fat diet (HFD) on the development of fetal metabolic systems. We found that fetal offspring from both lean and obese mothers chronically consuming a HFD had a 3-fold increase in liver triglycerides (TGs). In addition, fetal offspring from HFD-fed mothers (O-HFD) showed increased evidence of hepatic oxidative stress early in the third trimester, consistent with the development of nonalcoholic fatty liver disease (NAFLD). O-HFD animals also exhibited elevated hepatic expression of gluconeogenic enzymes and transcription factors. Furthermore, fetal glycerol levels were 2-fold higher in O-HFD animals than in control fetal offspring and correlated with maternal levels. The increased fetal hepatic TG levels persisted at P180, concurrent with a 2-fold increase in percent body fat. Importantly, reversing the maternal HFD to a low-fat diet during a subsequent pregnancy improved fetal hepatic TG levels and partially normalized gluconeogenic enzyme expression, without changing maternal body weight. These results suggest that a developing fetus is highly vulnerable to excess lipids, independent of maternal diabetes and/or obesity, and that exposure to this may increase the risk of pediatric NAFLD.
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PMID:Maternal high-fat diet triggers lipotoxicity in the fetal livers of nonhuman primates. 1914 84

There has been a marked increase in the number of babies born by elective CS (Caesarean section). Following CS, the lack of normal stimuli that occur at birth alters the thermogeneic response, but any effects on hepatic metabolism have not been identified. In the present study, we compared the effect of delivery on hepatic metabolism in piglets, born either by CS or VD (vaginal delivery) and fed by TPN (total parenteral nutrition), by measuring lipid metabolism and enzyme activity coupled with metabolomic and genomic approaches. Hepatic lipid in the CS piglets at 7 days post-partum was in excess of 5 mg/g of liver consistent with hepatic steatosis, whereas in the VD piglets the amount of lipid was markedly lower (3 mg/g of liver) and below the threshold for a diagnosis of steatosis. Metabolomic analysis indicated that CS resulted in higher hepatic glycerol and lower glycerol phosphate dehydrogenase activity, suggesting that CS causes a decrease in hepatic gluconeogenesis from glycerol. CS also resulted in altered cholesterol handling and gene expression, despite the same dietary intake for 7 days post-partum. Furthermore, the CS piglets had a lower expression of interferon-responsive genes, but a higher expression of markers of immature hepatocytes. In conclusion, the results suggest that VD promotes normal liver maturation and hepatic metabolism, thereby reducing the accumulation of hepatic lipid.
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PMID:Delivery by Caesarean section, rather than vaginal delivery, promotes hepatic steatosis in piglets. 1944 54

To determine whether inflammation can induce bovine fatty liver, we administered recombinant bovine tumor necrosis factor-alpha (rbTNF) to late-lactation Holstein cows. Cows (n = 5/treatment) were blocked by feed intake and parity and randomly assigned within block to control (CON; saline), rbTNF at 2 microg/(kg.d), or pair-fed control (saline, intake matched) treatments. Treatments were administered once daily by subcutaneous injection for 7 d. Plasma samples were collected daily for analysis of glucose and FFA and a liver biopsy was collected on d 7 for triglyceride (TG) and quantitative RT-PCR analyses. Data were analyzed using treatment contrasts to assess effects of tumor necrosis factor-alpha (TNFalpha) and decreased feed intake. By d 7, feed intake of both rbTNF and pair-fed cows was approximately 15% less than CON (P < 0.01). Administration of rbTNF resulted in greater hepatic TNFalpha mRNA and protein abundance and 103% higher liver TG content (P < 0.05) without affecting the plasma FFA concentration. Hepatic carnitine palmitoyltransferase 1 transcript abundance tended to be lower (P = 0.09) and transcript abundance of fatty acid translocase and 1-acyl-glycerol-3-phosphate acyltransferase was higher (both P < 0.05) after rbTNF treatment, consistent with increased FFA uptake and storage as TG. Transcript abundance of glucose-6-phosphatase (P < 0.05) and phosphoenolpyruvate carboxykinase 1 (P = 0.09), genes important for gluconeogenesis, was lower for rbTNF-treated cows. These findings indicate that TNFalpha promotes liver TG accumulation and suggest that inflammatory pathways may also be responsible for decreased glucose production in cows with fatty liver.
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PMID:Daily injection of tumor necrosis factor-{alpha} increases hepatic triglycerides and alters transcript abundance of metabolic genes in lactating dairy cattle. 1954 51

The nuclear receptor PPARalpha is activated by drugs to treat human disorders of lipid metabolism. Its endogenous ligand is unknown. PPARalpha-dependent gene expression is impaired with inactivation of fatty acid synthase (FAS), suggesting that FAS is involved in generation of a PPARalpha ligand. Here we demonstrate the FAS-dependent presence of a phospholipid bound to PPARalpha isolated from mouse liver. Binding was increased under conditions that induce FAS activity and displaced by systemic injection of a PPARalpha agonist. Mass spectrometry identified the species as 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (16:0/18:1-GPC). Knockdown of Cept1, required for phosphatidylcholine synthesis, suppressed PPARalpha-dependent gene expression. Interaction of 16:0/18:1-GPC with the PPARalpha ligand-binding domain and coactivator peptide motifs was comparable to PPARalpha agonists, but interactions with PPARdelta were weak and none were detected with PPARgamma. Portal vein infusion of 16:0/18:1-GPC induced PPARalpha-dependent gene expression and decreased hepatic steatosis. These data suggest that 16:0/18:1-GPC is a physiologically relevant endogenous PPARalpha ligand.
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PMID:Identification of a physiologically relevant endogenous ligand for PPARalpha in liver. 1964 43

The objective was to determine the effects of abomasal infusion of linseed oil on liver triglyceride (TG) accumulation and adipose tissue lipolysis during an experimental protocol for induction of fatty liver. Eight nonpregnant, nonlactating Holstein cows were randomly assigned to treatments in a replicated 4 x 4 Latin square design. Treatments were abomasal infusion of water (W), tallow (T), linseed oil (LO), or half linseed oil and half tallow (LOT) at a rate of 0.56 g/kg of body weight per day. Each experimental period consisted of a 4-d fast concurrent with administration of treatments into the abomasum in 6 equal doses per day (every 4 h). Cows were fed ad libitum for 24 d between periods of fasting and lipid infusion. Infusion of linseed oil (LO and LOT) increased alpha-linolenic acid (C18:3n-3) content in serum (12.2, 10.4, 4.2, and 4.6 g/100 g of fatty acids for LO, LOT, T, and W, respectively), but not in the nonesterified fatty acid (NEFA) fraction of plasma. Treatments had no effect on plasma NEFA concentrations. Abomasal infusion of lipid increased in vitro stimulated lipolysis in subcutaneous adipose tissue, compared with W (4,294, 3,809, 4,231, and 3,293 nmol of glycerol released x g(-1) tissue x 2 h(-1) for LO, LOT, T, and W, respectively), but there was no difference between fat sources. Hepatic TG accumulation over 4-d fast was 2.52, 2.60, 2.64, and 2.09 +/- 0.75 microg of TG/microg of DNA for W, LO, LOT, and T, respectively, which did not differ. Abomasal infusion of LO did not reduce liver TG accumulation, plasma NEFA concentration, or alter in vitro adipose tissue lipolysis when compared with T. These results contrast with a previous study involving i.v. infusion of lipid emulsion derived from LO. Discrepancies might be explained by the use of different administration routes and a relatively modest induction of liver TG accumulation in the current experiment.
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PMID:Effects of abomasal lipid infusion on liver triglyceride accumulation and adipose lipolysis during fatty liver induction in dairy cows. 1976 12

Comparative gene identification-58 (CGI-58), also designated as alpha/beta-hydrolase domain containing-5 (ABHD-5), is a lipid droplet-associated protein that activates adipose triglyceride lipase (ATGL) and acylates lysophosphatidic acid. Activation of ATGL initiates the hydrolytic catabolism of cellular triacylglycerol (TG) stores to glycerol and nonesterified fatty acids. Mutations in both ATGL and CGI-58 cause "neutral lipid storage disease" characterized by massive accumulation of TG in various tissues. The analysis of CGI-58-deficient (Cgi-58(-/-)) mice, presented in this study, reveals a dual function of CGI-58 in lipid metabolism. First, systemic TG accumulation and severe hepatic steatosis in newborn Cgi-58(-/-) mice establish a limiting role for CGI-58 in ATGL-mediated TG hydrolysis and supply of nonesterified fatty acids as energy substrate. Second, a severe skin permeability barrier defect uncovers an essential ATGL-independent role of CGI-58 in skin lipid metabolism. The neonatal lethal skin barrier defect is linked to an impaired hydrolysis of epidermal TG. As a consequence, sequestration of fatty acids in TG prevents the synthesis of acylceramides, which are essential lipid precursors for the formation of a functional skin permeability barrier. This mechanism may also underlie the pathogenesis of ichthyosis in neutral lipid storage disease patients lacking functional CGI-58.
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PMID:Growth retardation, impaired triacylglycerol catabolism, hepatic steatosis, and lethal skin barrier defect in mice lacking comparative gene identification-58 (CGI-58). 2002 87

The endocannabinoid system consists of endogenous arachidonic acid derivates that activate cannabinoid receptors. The two most prominent endocannabinoids are anandamide and 2-arachidonoyl glycerol. In obesity, increased concentrations of circulating and tissue endocannabinoid levels have been described, suggesting increased activity of the endocannabinoid system. Increased availability of endocannabinoids in obesity may over-stimulate cannabinoid receptors. Blockade of cannabinoid type 1 (CB1) receptors was the only successful clinical development of an anti-obesity drug during the last decade. Whereas blockade of CB1 receptors acutely reduces food intake, the long-term effects on metabolic regulation are more likely mediated by peripheral actions in liver, skeletal muscle, adipose tissue, and the pancreas. Lipogenic effects of CB1 receptor signalling in liver and adipose tissue may contribute to regional adipose tissue expansion and insulin resistance in the fatty liver. The association of circulating 2-arachidonoyl glycerol levels with decreased insulin sensitivity strongly suggests further exploration of the role of endocannabinoid signalling for insulin sensitivity in skeletal muscle, liver, and adipose tissue. A few studies have suggested a specific role for the regulation of adiponectin secretion from adipocytes by endocannabinoids, but that has to be confirmed by more experiments. Also, the potential role of CB1 receptor blockade for the stimulation of energy expenditure needs to be studied in the future. Despite the current discussion of safety issues of cannabinoid receptor blockade, these findings open a new and exciting perspective on endocannabinoids as regulators of body weight and metabolism.
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PMID:Peripheral metabolic effects of endocannabinoids and cannabinoid receptor blockade. 2005 57

Mammalian sirtuin 1 (SIRT1) may control fatty acid homeostasis in liver. However, this possibility and underlying mechanism remain to be established. In this study, we addressed the issues by examining the metabolic phenotypes of SIRT1 heterozygous knockout (SIRT1(+/-)) mice. The study was conducted in the mice on three different diets including a low-fat diet (5% fat wt/wt), mediate-fat diet (11% fat wt/wt), and high-fat diet (HFD, 36% fat wt/wt). On low-fat diet, the mice did not exhibit any abnormality. On mediate-fat diet, the mice exhibited a significant increase in hepatic steatosis with elevated liver/body ratio, liver size, liver lipid (triglyceride, glycerol, and cholesterol) content, and liver inflammation. The hepatic steatosis was deteriorated in the mice by HFD. In the liver, lipogenesis was increased, fat export was reduced, and beta-oxidation was not significantly changed. Body weight and fat content were increased in response to the dietary fat. Fat was mainly increased in sc adipose tissue and liver. Inflammation was also elevated in epididymal fat. Whole body energy expenditure and substrate utilization were reduced. Food intake, locomotor activity, and fat absorption were not changed. These data suggest that a reduction in the SIRT1 activity increases the risk of fatty liver in response to dietary fat. The liver steatosis may be a result of increased lipogenesis and reduced liver fat export. The inflammation may contribute to the pathogenesis of hepatic steatosis as well. A reduction in lipid mobilization may contribute to the hepatic steatosis and low energy expenditure.
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PMID:Lack of SIRT1 (Mammalian Sirtuin 1) activity leads to liver steatosis in the SIRT1+/- mice: a role of lipid mobilization and inflammation. 2033 25


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