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Dietary carote-noids like β-carotene are converted within the body either to retinoid, via β-carotene-15,15′-dioxygenase (BCO1), or to β-apo-carotenoids, via β-carotene-9′,10′-oxygenase 2. Some β-apo-carotenoids are po-tent antagonists of retinoic acid receptor (RAR)-mediated transcrip-tional regulation, which is required to ensure normal heart develop-ment and functions. We established liquid chromatography tandem mass spectrometery methods for measuring concentrations of 10 β-apo-carotenoids in mouse plasma, liver, and heart and assessed how these are influenced by Bco1 deficiency and β-carotene intake. Sur-prisingly, Bco1-/- mice had an increase in heart levels of retinol, nonesterified fatty acids, and ceramides and a decrease in heart triglycerides. These lipid changes were accompanied by elevations in levels of genes important to retinoid metabolism, specifically retinol dehydrogenase 10 and retinol-binding protein 4, as well as genes involved in lipid metabolism, including peroxisome proliferator-acti-vated receptor-7, lipoprotein lipase, Cd36, stearoyl-CoA desaturase 1, and fatty acid synthase. We also obtained evidence of compromised heart function, as assessed by two-dimensional echocardiography, in Bco1-/- mice. However, the total absence of Bco1 did not substan-tially affect β-apo-carotenoid concentrations in the heart. β-Carotene administration to matched Bco1-/- and wild-type mice elevated total β-apo-carotenal levels in the heart, liver, and plasma and total β-apo-carotenoic acid levels in the liver. Thus, BCO1 modulates heart metabolism and function, possibly by altering levels of cofactors required for the actions of nuclear hormone receptors. [ABSTRACT FROM AUTHOR]

Diacylglycerol acyltransferase 1 (DGAT1) catalyzes the final step in triglyceride synthesis, the conversion of diacylglycerol (DAG) to triglyceride. Dgat1-/- mice exhibit a number of beneficial metabolic effects including reduced obesity and improved insulin sensitivity and no known cardiac dysfunction. In contrast, failing human hearts have severely reduced DGAT1 expression associated with accumulation of DAGs and ceramides. To test whether DGAT1 loss alone affects heart function, we created cardiomyocyte-specific DGAT1 knock-out (hDgat1-/-) mice. hDgat1-/- mouse hearts had 95% increased DAG and 85% increased ceramides compared with floxed controls. 50% of these mice died by 9 months of age. The heart failure marker brain natriuretic peptide increased 5-fold in hDgat1-/- hearts, and fractional shortening (FS) was reduced. This was associated with increased expression of peroxisome proliferator-activated receptor α and cluster of differentiation 36. We crossed hDgat1-/- mice with previously described enterocyte-specific Dgat1 knock-out mice (hiDgat1-/-). This corrected the early mortality, improved FS, and reduced cardiac ceramide and DAG content. Treatment of hDgat1-/- mice with the glucagon-like peptide 1 receptor agonist exenatide also improved FS and reduced heart DAG and ceramide content. Increased fatty acid uptake into hDgat1-/- hearts was normalized by exenatide. Reduced activation of protein kinase Cα (PKCα), which is increased by DAG and ceramides, paralleled the reductions in these lipids. Our mouse studies show that loss of DGAT1 reproduces the lipid abnormalities seen in severe human heart failure. [ABSTRACT FROM AUTHOR]

Endotoxin, also called LPS, is a Gram-negative bacteria toxin that lowers circulating glucose in dogs, rabbits, rots and mice. Although LPS suppression of glucose has been studied for decades, the mechanism of this innate immune response and its significance in human health remain vague. Using gene-null mouse models, we found that TNFa, a proinflammatory plasma protein induced by LPS, is not required to lower glucose while TLR4 and MyD88, cell mediators in the induction of TNFa by LPS, represent obligatory components of the glucose lowering pathway. LPS lowered the appearance and utilization of circulating glucose in mice as well as glucose secretion in rat hepatocytes. In rat hepatoma cells, LPS lowered glucose production by activating PI3K and inhibiting NFkB. A single injection of LPS in wild-type mice, enhanced insulin suppression of circulating glucose however endotoxin tolerance, induced by more chronic LPS exposure, reduced insulin's ability to activate liver PI3K and lower glucose. Therefore, chronic TLR4 and MyD88 activation may contribute to the appearance of liver insulin resistance in people and the spread of type 2 diabetes. [ABSTRACT FROM AUTHOR]

Dietary carotenoids like β-carotene are converted within the body either to retinoid, via β-carotene-15,15'-dioxygenase (BCO1), or to β-apo-carotenoids, via β-carotene-9',10'-oxygenase 2. Some β-apo-carotenoids are potent antagonists of retinoic acid receptor (RAR)-mediated transcriptional regulation, which is required to ensure normal heart development and functions. We established liquid chromatography tandem mass spectrometery methods for measuring concentrations of 10 β-apo-carotenoids in mouse plasma, liver, and heart and assessed how these are influenced by Bco1 deficiency and β-carotene intake. Surprisingly, Bco1(-/-) mice had an increase in heart levels of retinol, nonesterified fatty acids, and ceramides and a decrease in heart triglycerides. These lipid changes were accompanied by elevations in levels of genes important to retinoid metabolism, specifically retinol dehydrogenase 10 and retinol-binding protein 4, as well as genes involved in lipid metabolism, including peroxisome proliferator-activated receptor-γ, lipoprotein lipase, Cd36, stearoyl-CoA desaturase 1, and fatty acid synthase. We also obtained evidence of compromised heart function, as assessed by two-dimensional echocardiography, in Bco1(-/-) mice. However, the total absence of Bco1 did not substantially affect β-apo-carotenoid concentrations in the heart. β-Carotene administration to matched Bco1(-/-) and wild-type mice elevated total β-apo-carotenal levels in the heart, liver, and plasma and total β-apo-carotenoic acid levels in the liver. Thus, BCO1 modulates heart metabolism and function, possibly by altering levels of cofactors required for the actions of nuclear hormone receptors., (Copyright © 2014 the American Physiological Society.)