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)

In a previous report (Langner, C. A., Birkenmeier, E. H., Ben-Zeev, O., Schotz, M. C., Sweet, H. O., Davisson, M. T., and Gordon, J. I. (1989) J. Biol. Chem. 264, 7994-8003), we characterized the early developmental phenotype of mice that were homozygous for the autosomal recessive fatty liver dystrophy (fld) mutation. Shortly after birth, these mice can be distinguished from their +/? littermates by large pale livers, hypertriglyceridemia, elevations in hepatic apolipoprotein A-IV and apoC-II mRNA levels, and tissue-specific decreases in lipoprotein lipase and hepatic lipase activities. These traits resolve by the early weaning period. We have now characterized a second feature of this mutation: a peripheral neuropathy that becomes manifest by an abnormal gait at the end of the second postnatal week and persists through adulthood. Electron microscopic studies of sciatic nerves from 4-day-to 1-year-old fld/fld mice demonstrated a variety of abnormalities including thin, poorly compacted myelin sheaths, active myelin breakdown, and enlarged Schwann cell mitochondria and nuclei. Western blot analysis of sciatic nerve homogenates prepared from 1 to 3-month-old fld/fld mice and their +/? littermates indicated that homozygous animals have striking reductions in two peripheral nerve myelin-associated proteins, P0 and P2. The steady-state level of apoE, a protein induced during nerve regeneration, is markedly elevated. Furthermore, two axon-specific proteins, neurofilament 68K and growth-associated 43 protein, display altered expression in adult fld/fld sciatic nerves. High performance thin-layer chromatography revealed deficiencies in phospholipids, glycosphingolipids, and some neutral lipids in fld/fld sciatic nerves harvested during the first several months of life (compared to their +/? littermates). Cholesterol esters were elevated in homozygotes. By contrast, no differences in brain lipids were noted between fld/fld animals and their +/? littermates. These data suggest that the fld mutation is associated with an abnormality of myelin formation (dysmyelination) as well as demyelination and axonal degeneration that persists despite apparent resolution of the neonatal hypertriglyceridemia and associated lipase abnormalities. These findings establish the fld/fld mouse as an excellent model system for analyzing homeostatic mechanisms that modulate lipid metabolism in newborn mice and for examining the pathogenesis of peripheral neuropathies associated with dyslipidemias.
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PMID:Characterization of the peripheral neuropathy in neonatal and adult mice that are homozygous for the fatty liver dystrophy (fld) mutation. 205 Jun 89

Hepatic apolipoprotein A-IV (apoA-IV) expression is correlated with hepatic triglyceride (TG) content in mouse models of chronic hepatosteatosis, and steatosis-induced hepatic apoA-IV gene expression is regulated by nuclear transcription factor cAMP-responsive element-binding protein H (CREBH) processing. To define what aspects of TG homeostasis regulate hepatic CREBH processing and apoA-IV gene expression, several mouse models of attenuated VLDL particle assembly were subjected to acute hepatosteatosis induced by an overnight fast or short term ketogenic diet feeding. Compared with chow-fed C57BL/6 mice, fasted or ketogenic diet-fed mice displayed increased hepatic TG content, which was highly correlated (r2 = 0.95) with apoA-IV gene expression, and secretion of larger, TG-enriched VLDL, despite a lower rate of TG secretion and a similar or reduced rate of apoB100 secretion. When VLDL particle assembly and secretion was inhibited by hepatic shRNA-induced apoB silencing or genetic or pharmacologic reduction in microsomal triglyceride transfer protein (MTP) activity, hepatic TG content increased dramatically; however, CREBH processing and apoA-IV gene expression were attenuated compared with controls. Adenovirus-mediated reconstitution of MTP expression proportionately restored CREBH processing and apoA-IV expression in liver-specific MTP knock-out mice. These results reveal that hepatic TG content, per se, does not regulate CREBH processing. Instead, TG mobilization into the endoplasmic reticulum for nascent VLDL particle assembly activates CREBH processing and enhances apoA-IV gene expression in the setting of acute steatosis. We conclude that VLDL assembly and CREBH activation play key roles in the response to hepatic steatosis by up-regulating apoA-IV and promoting assembly and secretion of larger, more TG-enriched VLDL particles.
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PMID:Very Low Density Lipoprotein Assembly Is Required for cAMP-responsive Element-binding Protein H Processing and Hepatic Apolipoprotein A-IV Expression. 2765 15

The molecular mechanism of stress-induced hepatic steatosis is not well known. Human leucine zipper protein (LZIP) regulates the expression of genes involved in inflammation, cell migration, and stress response. The aim of this study was to determine the regulatory role of LZIP in stress-induced hepatic steatosis. We used a microarray analysis to identify LZIP-induced genes involved in hepatic lipid metabolism. LZIP increased the expression of apolipoprotein A-IV (APOA4) mRNA. In the presence of stress inducer, APOA4 promoter analysis was performed, and LZIP-induced lipid accumulation was monitored in mouse primary cells and human tissues. Under Golgi stress conditions, LZIP underwent proteolytic cleavage and was phosphorylated by AKT to protect against proteasome degradation. The stabilized N-terminal LZIP was translocated to the nucleus, where it directly bound to the APOA4 promoter, leading to APOA4 induction. LZIP-induced APOA4 expression resulted in increased absorption of surrounding free fatty acids. LZIP also promoted hepatic steatosis in mouse liver. Both LZIP and APOA4 were highly expressed in human steatosis samples. Our findings indicate that LZIP is a novel modulator of APOA4 expression and hepatic lipid metabolism. LZIP might be a therapeutic target for developing treatment strategies for hepatic steatosis and related metabolic diseases.-Kang, M., Kim, J., An, H.-T., Ko, J. Human leucine zipper protein promotes hepatic steatosis via induction of apolipoprotein A-IV.
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PMID:Human leucine zipper protein promotes hepatic steatosis via induction of apolipoprotein A-IV. 2824 67