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)

Intragastric ethanol feeding in mice induces expression of unfolded protein response/endoplasmic reticulum (UPR/ER) stress response genes. The proximate cause appears to be hyperhomocysteinemia, a well-known cause of ER stress in other contexts. Hyperhomocysteinemia appears to be due to downregulation of methionine synthase. The importance of homocysteine and ER stress in the pathogenesis of liver disease was suggested by the prevention of the alcohol-induced changes by feeding sufficient betaine to lower homocysteine via betaine homocysteine methyl transferase. The ER stress, via CHOP, causes apoptosis and CHOP null mice exhibit no apoptosis. Alcohol-induced ER stress can activate sterol regulatory element-binding protein (SREBP)-1c and SREBP-2, which contribute to the accumulation of triglyceride and cholesterol. Hyperhomocysteinemia, ER stress and pathological changes of alcohol were minimally affected by absence of tumor necrosis factor receptor 1 (TNFR1) and the effect of betaine was also independent of TNF signaling. At present ER stress as an important factor in the pathogenesis of alcoholic liver disease is an exciting new hypothesis and ongoing research will need to further clarify its contribution. Among the issues in need of further elucidation are the role of ER stress induced by alcohol in SREBP regulation and fatty liver, as well as the precise mechanism of protection by betaine: decreased homocysteine, decreased S-adenosylhomocysteine, or increased S-adenosylmethionine.
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PMID:Unfolding new mechanisms of alcoholic liver disease in the endoplasmic reticulum. 1695 78

Total parenteral nutrition (TPN) induces a high rate of liver disease in infants, yet the pathogenesis remains elusive. We used neonatal piglets as an animal model to assess early events leading to TPN-mediated liver injury. Newborn piglets (n = 7) were nourished for 7 d on TPN or enteral nutrition (EN) and the liver tissue and isolated hepatocytes were subjected to morphologic and molecular analysis. Histological analysis revealed prominent steatosis (grade > 2) in 6 of 7 TPN pigs, whereas minimal steatosis (grade < or = 1) was observed in only 2 EN pigs. Abundant cytosolic cytochrome C and DNA fragmentation were observed in hepatocytes from TPN compared with EN piglets. Markers of mitochondrial and Fas-mediated apoptosis were altered in TPN liver tissue, as indicated by a lower ATP concentration (P < 0.05), accumulation of ubiquitin, 9.9-fold activation of caspase-3 activity (P < 0.01), and increased cleavage of poly-(ADP-ribose) polymerase, caspase-8, -9, and -7 when compared with EN livers. Bcl-2 and proliferating cell nuclear antigen expression was downregulated, whereas Fas and Bax were upregulated in TPN livers. However, levels of caspase-12 and Bip/GRP78, both markers of endoplasmic reticulum-mediated apoptosis, did not differ between the groups. Short-term TPN induces steatosis and oxidative stress, which results in apoptosis mediated by the mitochondrial and Fas pathways. Thus, TPN-induced steatosis in newborn piglets may serve as a novel animal model to assess the pathogenesis of fatty liver and apoptosis-mediated liver injury in infants.
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PMID:Total parenteral nutrition induces liver steatosis and apoptosis in neonatal piglets. 1698 24

Insulin has long-term effects on glucose and lipid metabolism through its control on the expression of specific genes. In insulin sensitive tissues and particularly in the liver, the transcription factor sterol regulatory element binding protein-1c (SREBP-1c) transduces the insulin signal. SREBP-1c is a transcription factor which is synthetized as a precursor in the membranes of the endoplasmic reticulum and which requires post-translational modification to yield its transcriptionally active nuclear form. Insulin activates the transcription and the proteolytic maturation of SREBP-1c. SREBP-1c induces the expression of a family of genes involved in glucose utilization and fatty acid synthesis and can be considered as a thrifty gene. Since a high lipid availability is deleterious for insulin sensitivity and secretion, a role for SREBP-1c in dyslipidaemia and type 2 diabetes has been considered in genetic studies and some association demonstrated. Finally, SREBP-1c could also participate to the hepatic steatosis observed in humans and related to alcohol consumption and hyperhomocysteinaemia, two pathologies which are concomitant with a stress of the endoplasmic reticulum and an insulin-independent SREBP-1c activation.
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PMID:SREBP-1c transcription factor and lipid homeostasis: clinical perspective. 1734 45

We evaluated the effects of a potent NO donor, S-nitroso-N-acetylcysteine (SNAC), on microsomal triglyceride transfer protein (MTP) expression in ob/ob mice. NAFLD was induced in male ob/ob mice using a methionine-choline deficient diet (MCD) concomitantly with oral SNAC fed solution (n=5) or vehicle (control; n=5) by gavage daily for 4 weeks. Livers were collected for histology and for assessing MTP by RT-qPCR, Western blot, immunohistochemistry and immunogold electron microscopy analyses. Histological analysis showed diffuse macro and microvesicular steatosis, moderate hepatocellular ballooning and moderate inflammatory infiltrate in ob/ob mice fed the MCD diet. With SNAC, mice showed a marked reduction in liver steatosis (p<0.01), in parenchymal inflammation (p=0.02) and in MTP protein immunoexpression in zone III (p=0.05). Moreover, SNAC caused reduction of MTP protein in Western blot analysis (p<0.05). In contrast, MTP mRNA content was significantly higher (p<0.05) in mice receiving SNAC. Immuno-electron microscopy showed MTP localized in the rough endoplasmic reticulum of hepatocytes in both treated and untreated groups. However with SNAC treatment, MTP was also observed surrounding fat globules. Histological improvement mediated by a nitric oxide donor is associated with significantly altered expression and distribution of MTP in this animal model of fatty liver disease. Further studies are in progress to examine possible mechanisms and to develop SNAC as a possible therapy for human fatty liver disease.
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PMID:Modulation of hepatic microsomal triglyceride transfer protein (MTP) induced by S-nitroso-N-acetylcysteine in ob/ob mice. 1752 68

The liver regulates lipid homeostasis and is enriched with natural killer T (NKT) cells that respond to lipid antigens. Optimal maturation and activation of NKT cells requires their interaction with lipid antigens that are presented by cluster of differentiation-1 (CD-1) molecules on antigen-presenting cells. Hepatocytes express CD1d and present lipid antigens to NKT cells. Depletion and dysregulation of hepatic NKT cells occurs in mice with fatty livers. Herein, we assess whether reduced CD1d content on steatotic hepatocytes contributes to fatty liver-associated NKT cell abnormalities. We show that despite expressing normal levels of CD1d mRNA, fatty hepatocytes from ob/ob mice have significantly less CD1d on their plasma membranes than normal hepatocytes. This has functional significance because ob/ob hepatocytes are less able to activate CD1d-restricted T-cell responses in vitro, and CD1d-reactive NKT cells are reduced in ob/ob livers. Events in the endoplasmic reticulum (ER) normally regulate CD1d trafficking to plasma membranes. Hepatic steatosis has been associated with ER stress. To determine if ER stress reduces CD-1 accumulation on hepatocytes, we evaluated hepatic ER stress in ob/ob mice and treated cultured hepatocytes and lean mice with tunicamycin to induce ER stress. Lipid accumulation and ER stress occurred in the livers of both ob/ob and tunicamycin-treated mice. Tunicamycin caused dose-dependent decreases in hepatocyte CD1d, inhibited hepatocyte activation of CD1d-restricted T-cell responses, depleted liver populations of CD1d-reactive NKT cells and promoted Th-1 polarization of hepatic cytokine production. In conclusion, ER stress-related decreases in hepatocyte CD1d contribute to NKT cell dysregulation in fatty livers.
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PMID:Endoplasmic reticulum stress, hepatocyte CD1d and NKT cell abnormalities in murine fatty livers. 1760

Triglycerides are insoluble in water and yet are transported at milligram per millilitre concentrations in the bloodstream. This is made possible by the ability of the liver and intestine to assemble lipid-protein emulsions (i.e. lipoproteins), which transport hydrophobic molecules. The assembly of triglyceride-rich lipoproteins requires the coordination of protein and lipid synthesis, which occurs on the cytoplasmic surface of the endoplasmic reticulum (ER), and their concerted assembly and translocation into the luminal ER secretory pathway as nascent lipoprotein particles. The availability of lipid substrate for triglyceride production and the machinery for lipoprotein assembly are highly sensitive to nutritional, hormonal, and genetic modulation. Disorders in lipid metabolism or an imbalance between lipogenesis and lipoprotein assembly can lead to hyperlipidemia and/or hepatic steatosis. We selectively review recently-identified machinery, such as transcription factors and nuclear hormone receptors, which provide new clues to the regulation of lipoprotein secretion.
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PMID:The physiological and molecular regulation of lipoprotein assembly and secretion. 1770 Aug 61

Endoplasmic reticulum stress, initiated by protein overload or malfolding, activates a complex network of interacting and parallel responses that dampen the stress. However, when the protective response is insufficient, a set of responses leads to apoptosis. Coupled with the latter are promotion of lipid synthesis and proinflammatory responses. Evidence has been mounting for an important role of the endoplasmic reticulum (ER) stress response in the pathogenesis of chronic viral hepatitis, insulin resistance and nonalcoholic fatty liver disease, ischemia-reperfusion injury, genetic disorders of protein malfolding, and alcoholic liver disease. In the latter, a key candidate for inducing ER stress is hyperhomocysteinemia. Betaine treatment promotes removal of homocysteine and prevents ER stress, fatty liver, and apoptosis in a mouse model of alcohol-induced liver disease. With increasing interest in the potential role of ER stress in liver disease, greater understanding of pathophysiology, prevention, and treatment of liver disease is anticipated.
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PMID:Endoplasmic reticulum stress and liver injury. 1797 73

Lipodystrophy is a disorder characterized by a loss of adipose tissue often accompanied by severe hypertriglyceridemia, insulin resistance, diabetes, and fatty liver. It can be inherited or acquired. The most severe inherited form is Berardinelli-Seip Congenital Lipodystrophy Type 2, associated with mutations in the BSCL2 gene. BSCL2 encodes seipin, the function of which has been entirely unknown. We now report the identification of yeast BSCL2/seipin through a screen to detect genes important for lipid droplet morphology. The absence of yeast seipin results in irregular lipid droplets often clustered alongside proliferated endoplasmic reticulum (ER); giant lipid droplets are also seen. Many small irregular lipid droplets are also apparent in fibroblasts from a BSCL2 patient. Human seipin can functionally replace yeast seipin, but a missense mutation in human seipin that causes lipodystrophy, or corresponding mutations in the yeast gene, render them unable to complement. Yeast seipin is localized in the ER, where it forms puncta. Almost all lipid droplets appear to be on the ER, and seipin is found at these junctions. Therefore, we hypothesize that seipin is important for droplet maintenance and perhaps assembly. In addition to detecting seipin, the screen identified 58 other genes whose deletions cause aberrant lipid droplets, including 2 genes encoding proteins known to activate lipin, a lipodystrophy locus in mice, and 16 other genes that are involved in endosomal-lysosomal trafficking. The genes identified in our screen should be of value in understanding the pathway of lipid droplet biogenesis and maintenance and the cause of some lipodystrophies.
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PMID:The lipodystrophy protein seipin is found at endoplasmic reticulum lipid droplet junctions and is important for droplet morphology. 1809 37

A wide range of factors can be attributed to the syndrome of fatty liver observed in some cultured fish species. The objective of the study was therefore to quantify different hepatocyte ultrastructural features as potentially influenced by twelve nutritional and husbandry factors, in order to discriminate the most influent factors in Eurasian perch (Perca fluviatilis), a typical carnivorous temperate fish species. Twenty-four groups of juveniles (initial weight 57.6 (SD 14.4) g) were intensively reared for 116 d and fed sixteen different isoproteic diets. The distribution of the experimental treatments was based on a multivariate fractional factorial design (L(24) 2(12)) with either high (+1) or low (-1) level of each of the following factors: diet (lipid and protein sources, lipid content, astaxanthin enrichment), feeding level, daily and weekly distribution frequency, fish density, initial weight heterogeneity, temperature, photoperiod, and light spectrum. Liver lipid droplets, glycogen, mitochondria and rough endoplasmic reticulum (RER) were semi-quantified and analysed by a soft imaging system using transmission electronic microscopy photographs. Important variability of hepatocyte ultrastructural features was observed. The present study confirms that the rearing temperature, through its influences in the general metabolic activity, seems to be the main factor modifying mainly lipid droplet accumulation and RER development. However, factors that could be pooled under the designation of factors leading to food accessibility and lipid and protein quality intensify or compensate the effect of temperature.
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PMID:Ultrastructural features of hepatocytes in cultured Eurasian perch ( Perca fluviatilis L.) as affected by nutritional and husbandry conditions. 1830 90

Ethanol induces the development of hepatic steatosis, increasingly recognized as causing vulnerability to subsequent liver injury. Ethanol has been shown to activate SREBP-1 (sterol regulatory element-binding protein) processing through the conventional cholesterol-sensitive pathway (1). The present study demonstrates that ethanol can also bring about SREBP-1 cleavage and activation through a novel pathway dependent on the endoplasmic reticulum-localized caspases-4 and -12. Evidence is presented that tumor necrosis factor can stimulate caspase-4 and -12 activation in ethanol-exposed cells, which cleaves SREBP-1 to a transcriptionally active form to induce the synthesis of lipogenic enzymes and triglycerides. Moreover, the caspase-4 and -12-dependent activation of SREBP-1 is insensitive to the normal negative feedback exerted by cholesterol and is mediated by the translocation of the scaffolding protein, TRAF-2, to the endoplasmic reticulum.
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PMID:Tumor necrosis factor-alpha can provoke cleavage and activation of sterol regulatory element-binding protein in ethanol-exposed cells via a caspase-dependent pathway that is cholesterol insensitive. 1863 49


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