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)

Persons heterozygous for Z, S and rare alpha-1-antitrypsin (AAT, SERPIN1A) polymorphisms (ca. 9% of population) are often considered 'silent' carriers with increased vulnerability to environmentally modulated liver and lung disease. They may have significantly more anxiety and bipolar spectrum disorders, nutritional compromise, and white matter disease [Schmechel DE, Browndyke J, Ghio A. Strategies for the dissection of genetic-environmental interactions in neurodegenerative disorders. Neurotoxicology 2006;27:637-57]. Given association of art and mood disorders, we examined occupation and artistic vocation from this same series. One thousand five hundred and thirty-seven consecutive persons aged 16-90 years old received comprehensive work-up including testing for AAT 'phenotype' and level, nutritional factors, and inflammatory, iron and copper indices. Occupations were grouped by Bureau of Labor Standards classification and information gathered on artistic activities. Proportion of reactive airway disease, obstructive pulmonary disease, and pre-existing anxiety disorder or bipolar disorder were significantly increased in persons carrying AAT non-M polymorphisms compared to normal MM genotype (respectively, 10, 20, 21, and 33% compared to 8, 12, 11, and 9%; contingency table, pulmonary: chi2 37, p=0.0001; affective disorder: chi2=171, p=0.0001). In persons with artistic avocation (n=189) or occupation (n=57), AAT non-M polymorphisms are significantly increased (respectively, proportions of 44 and 40% compared to background rate of 9%; contingency table, avocation: chi2=172, p=0.0001; occupation: chi2=57, p=0.0007). Artistic ability and 'anxiety/bipolar spectrum' mood disorders may represent phenotypic attributes that had selective advantage during recent human evolution, an 'intensive creative energy' (ICE) behavioral phenotype. Background proportion of ICE of 7% consists of 49 of 1312 persons with AAT MM genotype (4%), and 58 of 225 persons with non-MM genotypes (26%) (contingency table, chi2=222, p=0.0001). Penetrance of ICE increases in genotypes with lower AAT levels: PiMS, 18%; PiMZ, 44%; PiSS and PiZZ, 100% (five cases). At all ages, persons with non-MM genotype had significantly higher proportion of thiamine deficiency (50% in PiMZ), reactive hypoglycemia (20% in PiMZ), and possibly fatty liver (thiamine: chi2=28, p=0.0001; hypoglycemia: chi2=92, p=0.0001). In older persons, PiMZ genotype had significantly increased proportion (46%) of brain MRI T2 white matter abnormalities (chi2=49, p=0.003). Persons with ICE and MM genotype showed increased prevalence of pulmonary disorders and same signature as S and Z carriers and homozygotes (see above). Z polymorphism was associated with delayed age of onset (average 7 years) for persons with toxic environmental or occupational exposures (log rank, p=0.0001) and more stable cognitive change in persons with neurodegenerative illness (p<0.05). At all ages, ICE phenotype and Z polymorphism were associated with altered copper homeostasis with low or absent non-ceruloplasmin bound copper (p<0.05). AAT polymorphisms which affect iron, lipid and copper metabolism may affect early events in nervous system development, function and response to environmental exposures. AAT may also be a 'switch' for copper metabolism and low 'free' copper would be theorized to provide protection for lipid oxidation and favorably affect beta-amyloid and other aggregation, but possibly alter early 'critical' period of CNS development. AAT polymorphisms may define an important and treatable subset of persons presenting with CNS disorders. This new proposed phenotype for AAT transcends classic pattern of strictly liver and lung disease, and should be considered for proper evaluation and management of patients presenting with classic AAT-related disorders, affective disorders, persons with ICE, white matter disease or multisystem disorders of memory.
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PMID:Art, alpha-1-antitrypsin polymorphisms and intense creative energy: blessing or curse? 1765 42

Organic cation transporter 1, OCT1 (SLC22A1), is the major hepatic uptake transporter for metformin, the most prescribed antidiabetic drug. However, its endogenous role is poorly understood. Here we show that similar to metformin treatment, loss of Oct1 caused an increase in the ratio of AMP to ATP, activated the energy sensor AMP-activated kinase (AMPK), and substantially reduced triglyceride (TG) levels in livers from healthy and leptin-deficient mice. Conversely, livers of human OCT1 transgenic mice fed high-fat diets were enlarged with high TG levels. Metabolomic and isotopic uptake methods identified thiamine as a principal endogenous substrate of OCT1. Thiamine deficiency enhanced the phosphorylation of AMPK and its downstream target, acetyl-CoA carboxylase. Metformin and the biguanide analog, phenformin, competitively inhibited OCT1-mediated thiamine uptake. Acute administration of metformin to wild-type mice reduced intestinal accumulation of thiamine. These findings suggest that OCT1 plays a role in hepatic steatosis through modulation of energy status. The studies implicate OCT1 as well as metformin in thiamine disposition, suggesting an intriguing and parallel mechanism for metformin and its major hepatic transporter in metabolic function.
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PMID:OCT1 is a high-capacity thiamine transporter that regulates hepatic steatosis and is a target of metformin. 2496 73

The food habit is involved in the onset and development of lifestyle-related diseases. In this review I would like to describe a historical case of vitamin B1 deficiency, as well as our case study of fatty acid metabolism abnormality due to carnitine deficiency. In history, the army and navy personnel in Japan at the end of the 19th century received food rations based on a high-carbohydrate diet including white rice, resulting in the onset of beriberi. An epidemiological study by Kenkan Takaki revealed the relationship between the onset of beriberi and rice intake. Then, Takaki was successful in preventing the onset of beriberi by changing the diet. However, the primary cause had yet to be elucidated. Finally, Christian Eijkman established an animal model of beriberi (chickens) showing peripheral neuropathy, and he identified the existence of an anti-beriberi substance, vitamin B1. This is an example of the successful control of a disease by integrating the results of epidemiological and experimental studies. In our study using a murine model of fatty acid metabolism abnormality caused by carnitine deficiency, cardiac abnormality and fatty liver developed depending on the amount of dietary fat. In addition, the mice showed disturbance of orexin neuron activity related to the sleep-arousal system, which is involved in fatigue symptoms under fasting condition, one of the states showing enhanced fatty acid metabolism. These findings suggest that fatty acid toxicity is enhanced when the mice are more dependent on fatty acid metabolism. Almost simultaneously, a human epidemiological study showed that narcolepsy, which is caused by orexin system abnormality, is associated with the polymorphism of the gene coding for carnitine palmitoyltransferase 1B, which is involved in carnitine metabolism. To understand the pathological mechanism of fatty acid toxicity, not only an experimental approach using animal models, but also an epidemiological approach is necessary. The results will be applied to preventing and treating lifestyle-related diseases associated with fatty acid metabolism abnormality.
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PMID:[Experimental Approach to Analysis of the Relationship between Food Environments and Lifestyle-Related Diseases, Including Cardiac Hypertrophy, Fatty Liver, and Fatigue Symptoms]. 2599 41