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)

Deciphering novel pathways regulating liver lipid content has profound implications for understanding the pathophysiology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Recent evidence suggests that the nuclear envelope is a site of regulation of lipid metabolism but there is limited appreciation of the responsible mechanisms and molecular components within this organelle. We showed that conditional hepatocyte deletion of the inner nuclear membrane protein lamina-associated polypeptide 1 (LAP1) caused defective VLDL secretion and steatosis, including intranuclear lipid accumulation. LAP1 binds to and activates torsinA, an AAA+ ATPase that resides in the perinuclear space and continuous main ER. Deletion of torsinA from mouse hepatocytes caused even greater reductions in VLDL secretion and profound steatosis. Both of these mutant mouse lines developed hepatic steatosis and subsequent steatohepatitis on a regular chow diet in the absence of whole-body insulin resistance or obesity. Our results establish an essential role for the nuclear envelope-localized torsinA-LAP1 complex in hepatic VLDL secretion and suggest that the torsinA pathway participates in the pathophysiology of nonalcoholic fatty liver disease.
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PMID:Nuclear envelope-localized torsinA-LAP1 complex regulates hepatic VLDL secretion and steatosis. 3158 64

Elevated free fatty acids, particularly saturated ones such as palmitic acid, may play an important role in the lipotoxic mechanism of nonalcoholic fatty liver disease (NAFLD). Saturated fatty acids induce autophagy dysfunction and endoplasmic reticulum (ER) stress leading to apoptosis in hepatocytes. However, unsaturated fatty acids, such as oleic acid, are nontoxic and can even prevent saturated fatty acid-induced toxicity in vitro. Although emerging evidence has suggested that ER calcium flux disruption in hepatocytes is involved in NAFLD pathogenesis, the roles of fatty acids in autophagy and ER calcium flux still remain unclear. We demonstrated that oleic acid ameliorated palmitic acid-induced autophagy arrest and ER stress in parallel with ER calcium depletion in hepatocytes. Moreover, we found that the effect of oleic acid against autophagy arrest was reversed by the pharmacological inhibition of sarcoplasmic reticulum Ca2+-ATPase (SERCA), which influxes calcium to ER. These data suggest that SERCA-mediated ER calcium flux is greatly involved in fatty acid-induced lipotoxicity in hepatocytes, and the prevention of ER calcium depletion may restore saturated fatty acid-induced autophagy arrest in hepatocytes.
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PMID:Involvement of sarco/endoplasmic reticulum calcium ATPase-mediated calcium flux in the protective effect of oleic acid against lipotoxicity in hepatocytes. 3156 62

Mutations affecting the integrity of the essential torsin ATPase/cofactor system have been identified in a steadily increasing number of congenital disorders. Since most of these mutations affect brain function, much of the research has focused on deciphering disease etiology in the brain. However, torsin is expressed in a wide variety of nonneural tissues and is strictly conserved across species, including the lowest metazoans, suggesting that it plays roles extending beyond neurons. In this issue of the JCI, Shin et al. explored torsin function in the mammalian liver. The group reports major defects in hepatic lipid metabolism when the torsin system is compromised in mice. Remarkably, conditional deletion of either torsinA or its cofactor, lamina-associated polypeptide 1 (LAP1), resulted in fatty liver disease and steatohepatitis, likely from a secretion defect of VLDLs. This study considerably expands our understanding of torsin biology, while providing defined opportunities for future investigations of torsin function and dysfunction in human pathologies.
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PMID:An unbiased approach de-livers unexpected insight into torsin biology. 3140 37

The V-ATPase is a multi-subunit protein complex required for acidification of intracellular compartments. At least five different factors are known to be essential for its assembly in the endoplasmic reticulum. Genetic defects in four of these V-ATPase assembly factors show overlapping clinical features, including steatotic liver disease and mild hypercholesterolemia. An exception is the assembly factor VMA21 whose X-linked mutations lead to autophagic myopathy. Here, we report pathogenic variants in VMA21 in male patients with abnormal protein glycosylation that result in mild cholestasis, chronic elevation of transaminases, elevation of (LDL) cholesterol and steatosis in hepatocytes. We also show that the VMA21 variants lead to V-ATPase misassembly and dysfunction. As consequence, lysosomal acidification and degradation of phagocytosed materials are impaired causing lipid droplet (LD) accumulation in autolysosomes. Moreover, VMA21 deficiency triggers ER stress and sequestration of unesterified cholesterol in lysosomes, thereby activating the sterol response element-binding protein (SREBP)-mediated cholesterol synthesis pathways. Conclusion: Together, our data suggest that impaired lipophagy, ER stress and increased cholesterol synthesis lead to LD accumulation and hepatic steatosis. V-ATPase assembly defects are thus a novel form of hereditary liver disease with implications for the pathogenesis of non-alcoholic fatty liver disease.
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PMID:sMutations in the V-ATPase assembly factor VMA21 cause a congenital disorder of glycosylation with autophagic liver disease. 3214 91

Genome-wide association studies (GWAS) have linked IGF2BP2 single-nucleotide polymorphisms (SNPs) with type 2 diabetes (T2D). Mice overexpressing mIGF2BP2 have elevated cholesterol levels when fed a diet that induces hepatic steatosis. These and other studies suggest an important role for insulin growth factor 2 mRNA binding protein 2 (IGF2BP2) in the initiation and progression of several metabolic disorders. The ATPase binding cassette protein ABCA1 initiates nascent high-density apolipoprotein (HDL) biogenesis by transferring phospholipid and cholesterol to delipidated apolipoprotein AI (ApoAI). Individuals with mutational ablation of ABCA1 have Tangier disease, which is characterized by a complete loss of HDL. MicroRNA 33a and 33b (miR-33a/b) bind to the 3' untranslated region (UTR) of ABCA1 and repress its posttranscriptional gene expression. Here, we show that IGF2BP2 works together with miR-33a/b in repressing ABCA1 expression. Our data suggest that IGF2BP2 is an accessory protein of the argonaute (AGO2)-miR-33a/b-RISC complex, as it directly binds to miR-33a/b, AGO2, and the 3' UTR of ABCA1 Finally, we show that mice overexpressing human IGF2BP2 have decreased ABCA1 expression, increased low-density lipoprotein-cholesterol (LDL-C) and cholesterol blood levels, and elevated SREBP-dependent signaling. Our data support the hypothesis that IGF2BP2 has an important role in maintaining lipid homeostasis through its modulation of ABCA1 expression, as its overexpression or loss leads to dyslipidemia.
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PMID:Human Insulin Growth Factor 2 mRNA Binding Protein 2 Increases MicroRNA 33a/b Inhibition of Liver ABCA1 Expression and Alters Low-Density Apolipoprotein Levels in Mice. 3248 98


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