ENU mutagenesis identifies mice with cardiac fibrosis and hepatic steatosis caused by a mutation in the mitochondrial trifunctional protein beta-subunit.
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Using the metabolomics-guided screening coupled to N-ethyl-N-nitrosourea-mediated mutagenesis, we identified mice that exhibited elevated levels of long-chain acylcarnitines. Whole genome homozygosity mapping with 262 SNP markers mapped the disease gene to chromosome 5 where candidate genes Hadha and Hadhb, encoding the mitochondria trifunctional protein (MTP) alpha- and beta-subunits, respectively, are located. Direct sequencing revealed a normal alpha-subunit, but detected a nucleotide T-to-A transversion in exon 14 (c.1210T>A) of beta-subunit (Hadhb) which resulted in a missense mutation of methionine to lysine (M404K). Western blot analysis showed a significant reduction of both the alpha- and beta-subunits, consistent with reduced enzyme activity in both the long-chain 3-hydroxyacyl-CoA dehydrogenase and the long-chain 3-ketoacyl-CoA thiolase activities. These mice had a decreased weight gain and cardiac arrhythmias which manifested from a prolonged PR interval to a complete atrio-ventricular dissociation, and died suddenly between 9 and 16 months of age. Histopathological studies showed multifocal cardiac fibrosis and hepatic steatosis. This mouse model will be useful to further investigate the mechanisms underlying arrhythmogenesis relating to lipotoxic cardiomyopathy and to investigate pathophysiology and treatment strategies for human MTP deficiency. (+info)
Stearoyl-CoA desaturase-1 mediates the pro-lipogenic effects of dietary saturated fat.
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Dietary saturated fats have often been implicated in the promotion of obesity and related disorders. It has been shown recently that saturated fats act through the transcription factor SREBP-1c (sterol regulatory element-binding protein-1c) and its requisite coactivator, peroxisome proliferator-activated receptor-gamma coactivator-1beta (PGC-1beta), to exert their pro-lipogenic effects. We show here that a diet high in the saturated fat stearate induces lipogenic genes in wild-type mice, with the induction of the Scd1 (stearoyl-CoA desaturase-1) gene preceding that of other lipogenic genes. However, in Scd1-/- mice, stearate does not induce lipogenesis, and Srebp-1c and Pgc-1beta levels are markedly reduced. Instead, genes of fatty acid oxidation such as Cpt-1 (carnitine palmitoyltransferase-1) as well as Pgc-1alpha are induced. Mitochondrial fatty acid oxidation is increased, and white adipose tissue and hepatic glycogen stores are depleted in stearate-fed Scd1-/- mice. Furthermore, AMP-activated protein kinase is also induced by stearate feeding in Scd1-/- mice. These results indicate that the desaturation of saturated fats such as stearate by SCD is an essential step mediating their induction of lipogenesis. In the absence of SCD1, stearate promotes oxidation, leading to protection from saturated fat-induced obesity. SCD1 thus serves as a molecular switch in the promotion or prevention of lipid-induced disorders brought on by consumption of excess saturated fat. (+info)
Disordered lipid metabolism and the pathogenesis of insulin resistance.
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Although abnormal glucose metabolism defines type 2 diabetes mellitus (T2DM) and accounts for many of its symptoms and complications, efforts to understand the pathogenesis of T2DM are increasingly focused on disordered lipid metabolism. Here we review recent human studies exploring the mechanistic links between disorders of fatty acid/lipid metabolism and insulin resistance. As "mouse models of insulin resistance" were comprehensively reviewed in Physiological Reviews by Nandi et al. in 2004, we will concentrate on human studies involving the use of isotopes and/or magnetic resonance spectroscopy, occasionally drawing on mouse models which provide additional mechanistic insight. (+info)
Hyperammonemic encephalopathy caused by carnitine deficiency.
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Carnitine is an essential co-factor in fatty acid metabolism. Carnitine deficiency can impair fatty acid oxidation, rarely leading to hyperammonemia and encephalopathy. We present the case of a 35-year-old woman who developed acute mental status changes, asterixis, and diffuse muscle weakness. Her ammonia level was elevated at 276 microg/dL. Traditional ammonia-reducing therapies were initiated, but proved ineffective. Pharmacologic, microbial, and autoimmune causes for the hyperammonemia were excluded. The patient was severely malnourished and her carnitine level was found to be extremely low. After carnitine supplementation, ammonia levels normalized and the patient's mental status returned to baseline. In the setting of refractory hyperammonemia, this case illustrates how careful investigation may reveal a treatable condition. (+info)
ApoB100,LDLR-/- mice exhibit reduced electroretinographic response and cholesteryl esters deposits in the retina.
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Carbohydrate and lipid disorders and relevant considerations in persons with spinal cord injury.
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OBJECTIVES: To assess the prevalence of carbohydrate and lipid disorders in adults with chronic spinal cord injury and evaluate their risk contribution to cardiovascular diseases and the potential impact of exercise and pharmacologic and dietary therapies to alter these disorders and reduce cardiovascular disease risk. DATA SOURCES: MEDLINE (PubMed), Cochrane Database and Web sites of the American Spinal Injury Association, American Paraplegia Society, Paralyzed Veterans of America, Consortium of Spinal Cord Medicine, and WorldCat through August 2007. REVIEW METHODS: English language observational studies addressing prevalence of carbohydrate and lipid disorders were included if they evaluated at least 100 adults with chronic spinal cord injury or a total of 100 subjects if using a control group. Epidemiologic investigations of more than 50 adults with spinal cord injury that were published in English after 1990 and reported cardiovascular morbidity and mortality were abstracted. Intervention studies from 1996-2007 were included regardless of design or size if they assessed exercise, diet, or pharmacologic therapies and reported carbohydrate, lipid, or cardiovascular outcomes. RESULTS: The quality of evidence regarding the prevalence, impact, and outcomes of carbohydrate and lipid disorders in adults with chronic spinal cord injuries is weak. Evidence is limited by relatively few studies, small sample size, lack of appropriate control groups, failure to adjust for known confounding variables, and variation in reported outcomes. However, the existing evidence does not indicate that adults with spinal cord injuries are at markedly greater risk for carbohydrate and lipid disorders or subsequent cardiovascular morbidity and mortality than able-bodied adults. Body mass index is not reliable for assessing body composition, especially percent body fat, in adults with spinal cord injury. There are no high quality studies evaluating the impact of exercise, diet, or pharmacologic therapies on these disorders. CONCLUSIONS: The available evidence does not support incorporating SCI status as an independent variable to assess risk of cardiovascular morbidity and mortality or to alter diagnostic/treatment thresholds compared to able-bodied adults. Furthermore, individuals with SCI may have unique physiologic differences compared to able-bodied individuals. As a result, it is uncertain that findings from studies conducted in able-bodied adults evaluating efficacy and harms of interventions to improve carbohydrate, lipid disorders, and subsequent CVD can be extrapolated to individuals with SCI. The role of exercise in individuals with spinal cord injuries represents a unique challenge and requires further exploration into the benefits, harms, and resource implications of broad-based spinal cord injury exercise programs. (+info)
Hormonal contraception and HIV-positive women: metabolic concerns and management strategies.
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