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)

Large-scale epidemiological studies show that low exercise capacity is the highest risk factor for all-cause morbidity and mortality relative to other conditions including diabetes, hypertension, and obesity. This led us to formulate the energy transfer hypothesis (ETH): Variation in capacity for energy transfer is the central mechanistic determinant of the divide between disease and health. As a test of this hypothesis, we predicted that two-way selective breeding of genetically heterogeneous rats for low and high intrinsic treadmill running capacity (a surrogate for energy transfer) would also produce rats that differ for disease risks. The lines are termed low-capacity runners (LCRs) and high-capacity runners (HCRs) and, after 36 generations of selection, they differ by more than eightfold in running capacity. Consistent with the ETH, the LCRs score high for developing disease risks, including metabolic syndrome, neurodegeneration, cognitive impairment, fatty liver disease, susceptibility to cancer, and reduced longevity. The HCRs are resistant to the development of these disease risks. Here we synthesize ideas on nonequilibrium thermodynamics and evolution from Ilya Prigogine, Hans Krebs, and Peter Mitchell to formulate theoretic explanations for the ETH. First, at every moment in time, the atoms and molecules of organisms are reorganizing to pursue avenues for energy transfer. Second, this continuous organization is navigating in a constantly changing environment such that "strategies" are perpetually in flux and do not leave a simple footprint (evolution). Third, as a consequence, human populations demonstrate a wide variation in capacity for energy transfer that mirrors mechanistically the divide between disease and health.
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PMID:Theoretical and Biological Evaluation of the Link between Low Exercise Capacity and Disease Risk. 2838 12

Perilipin 2 (PLIN2) is a lipid-droplet protein that is up-regulated in alcoholic steatosis and associated with hepatic accumulation of ceramides, bioactive lipids implicated in alcoholic liver disease pathogenesis. The specific role of ceramide synthetic enzymes in the regulation of PLIN2 and promotion of hepatocellular lipid accumulation is not well understood. We examined the effects of pharmacologic ceramide synthesis inhibition on hepatic PLIN2 expression, steatosis, and glucose and lipid homeostasis in mice with alcoholic steatosis and in ethanol-incubated human hepatoma VL17A cells. In cells, pharmacologic inhibition of ceramide synthase reduced lipid accumulation by reducing PLIN2 RNA stability. The subtype ceramide synthase (CerS)6 was specifically up-regulated in experimental alcoholic steatosis in vivo and in vitro and was up-regulated in zone 3 hepatocytes in human alcoholic steatosis. In vivo ceramide reduction by inhibition of de novo ceramide synthesis reduced PLIN2 and hepatic steatosis in alcohol-fed mice, but only de novo synthesis inhibition, not sphingomyelin hydrolysis, improved glucose tolerance and dyslipidemia. These findings implicate CerS6 as a novel regulator of PLIN2 and suggest that ceramide synthetic enzymes may promote the earliest stage of alcoholic liver disease, alcoholic steatosis.-Williams, B., Correnti, J., Oranu, A., Lin, A., Scott, V., Annoh, M., Beck, J., Furth, E., Mitchell, V., Senkal, C. E., Obeid, L., Carr, R. M. A novel role for ceramide synthase 6 in mouse and human alcoholic steatosis.
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PMID:A novel role for ceramide synthase 6 in mouse and human alcoholic steatosis. 2886 59