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)

Clinical studies have shown a close association between nonalcoholic fatty liver disease and adult-onset GH deficiency, but the relevant molecular mechanisms are still unclear. No mouse model has been suitable to study the etiological relationship of human nonalcoholic fatty liver disease and human adult-onset GH deficiency under conditions similar to the human liver in vivo. We generated human (h-)hepatocyte chimeric mice with livers that were predominantly repopulated with h-hepatocytes in a h-GH-deficient state. The chimeric mouse liver was mostly repopulated with h-hepatocytes about 50 d after transplantation and spontaneously became fatty in the h-hepatocyte regions after about 70 d. Infusion of the chimeric mouse with h-GH drastically decreased steatosis, showing the direct cause of h-GH deficiency in the generation of hepatic steatosis. Using microarray profiles aided by real-time quantitative RT-PCR, comparison between h-hepatocytes from h-GH-untreated and -treated mice identified 14 GH-up-regulated and four GH-down-regulated genes, including IGF-I, SOCS2, NNMT, IGFLS, P4AH1, SLC16A1, SRD5A1, FADS1, and AKR1B10, respectively. These GH-up- and -down-regulated genes were expressed in the chimeric mouse liver at lower and higher levels than in human livers, respectively. Treatment of the chimeric mice with h-GH ameliorated their altered expression. h-Hepatocytes were separated from chimeric mouse livers for testing in vitro effects of h-GH or h-IGF-I on gene expression, and results showed that GH directly regulated the expression of IGF-I, SOCS2, NNMT, IGFALS, P4AH1, FADS1, and AKR1B10. In conclusion, the chimeric mouse is a novel h-GH-deficient animal model for studying in vivo h-GH-dependent human liver dysfunctions.
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PMID:Growth hormone-dependent pathogenesis of human hepatic steatosis in a novel mouse model bearing a human hepatocyte-repopulated liver. 2130 49

MAF1 is a global repressor of RNA polymerase III transcription that regulates the expression of highly abundant noncoding RNAs in response to nutrient availability and cellular stress. Thus, MAF1 function is thought to be important for metabolic economy. Here we show that a whole-body knockout of Maf1 in mice confers resistance to diet-induced obesity and nonalcoholic fatty liver disease by reducing food intake and increasing metabolic inefficiency. Energy expenditure in Maf1(-/-) mice is increased by several mechanisms. Precursor tRNA synthesis was increased in multiple tissues without significant effects on mature tRNA levels, implying increased turnover in a futile tRNA cycle. Elevated futile cycling of hepatic lipids was also observed. Metabolite profiling of the liver and skeletal muscle revealed elevated levels of many amino acids and spermidine, which links the induction of autophagy in Maf1(-/-) mice with their extended life span. The increase in spermidine was accompanied by reduced levels of nicotinamide N-methyltransferase, which promotes polyamine synthesis, enables nicotinamide salvage to regenerate NAD(+), and is associated with obesity resistance. Consistent with this, NAD(+) levels were increased in muscle. The importance of MAF1 for metabolic economy reveals the potential for MAF1 modulators to protect against obesity and its harmful consequences.
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PMID:Loss of the RNA polymerase III repressor MAF1 confers obesity resistance. 2593 5

Nicotinamide N-methyltransferase (NNMT) catalyses the reaction between nicotinamide (NAM) and S-adenosylmethionine to produce 1-methylnicotinamide and S-adenosylhomocysteine. Recently, this enzyme has also been reported to modulate hepatic nutrient metabolism, but its role in the liver has not been fully elucidated. We developed transgenic mice overexpressing NNMT to elucidate its role in hepatic nutrient metabolism. When fed a high fat diet containing NAM, a precursor for nicotinamide adenine dinucleotide (NAD)+, these NNMT-overexpressing mice exhibit fatty liver deterioration following increased expression of the genes mediating fatty acid uptake and decreased very low-density lipoprotein secretion. NNMT overactivation decreased the NAD+ content in the liver and also decreased gene activity related to fatty acid oxidation by inhibiting NAD+-dependent deacetylase Sirt3 function. Moreover, the transgenic mice showed liver fibrosis, with the induction of inflammatory and fibrosis genes. Induced NNMT expression decreased the tissue methylation capacity, thereby reducing methylation of the connective tissue growth factor (CTGF) gene promoter, resulting in increased CTGF expression. These data indicate that NNMT links the NAD+ and methionine metabolic pathways and promotes liver steatosis and fibrosis. Therefore, targeting NNMT may serve as a therapeutic strategy for treating fatty liver and fibrosis.
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PMID:NNMT activation can contribute to the development of fatty liver disease by modulating the NAD + metabolism. 2987 22

Abnormal hepatic insulin signaling is a cause or consequence of hepatic steatosis. DPP-4 inhibitors might be protective against fatty liver. We previously reported that the systemic inhibition of insulin receptor (IR) and IGF-1 receptor (IGF1R) by the administration of OSI-906 (linsitinib), a dual IR/IGF1R inhibitor, induced glucose intolerance, hepatic steatosis, and lipoatrophy in mice. In the present study, we investigated the effects of a DPP-4 inhibitor, linagliptin, on hepatic steatosis in OSI-906-treated mice. Unlike high-fat diet-induced hepatic steatosis, OSI-906-induced hepatic steatosis is not characterized by elevations in inflammatory responses or oxidative stress levels. Linagliptin improved OSI-906-induced hepatic steatosis via an insulin-signaling-independent pathway, without altering glucose levels, free fatty acid levels, gluconeogenic gene expressions in the liver, or visceral fat atrophy. Hepatic quantitative proteomic and phosphoproteomic analyses revealed that perilipin-2 (PLIN2), major urinary protein 20 (MUP20), cytochrome P450 2b10 (CYP2B10), and nicotinamide N-methyltransferase (NNMT) are possibly involved in the process of the amelioration of hepatic steatosis by linagliptin. Thus, linagliptin improved hepatic steatosis induced by IR and IGF1R inhibition via a previously unknown mechanism that did not involve gluconeogenesis, lipogenesis, or inflammation, suggesting the non-canonical actions of DPP-4 inhibitors in the treatment of hepatic steatosis under insulin-resistant conditions.
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PMID:Linagliptin Ameliorates Hepatic Steatosis via Non-Canonical Mechanisms in Mice Treated with a Dual Inhibitor of Insulin Receptor and IGF-1 Receptor. 3310 4