24 Hyperinsulinemia induces hepatic SREBP-1c expression while hyp

24 Hyperinsulinemia induces hepatic SREBP-1c expression while hyperglycemia stimulates ChREBP activity. These events lead to transcriptional activation of all lipogenic genes including adenosine triphosphate selleck products citrate lyase, acetyl-CoA carboxylase, and FAS,25 effectively increasing FAS flux. Because citrate formed in the TCA cycle and shuttled to the cytosol is the primary metabolite required in the production of fatty acids, there is inevitably an increase in demand for this intermediate. Therefore, it is unsurprising that a recent 13C isotopomer

study found a 2-fold increase of hepatic TCA cycle flux in patients with nonalcoholic fatty liver disease.26 Because only pyruvate that enters the TCA cycle through PC produces a net increase in cycle intermediates, whereas pyruvate entering through PDH is restricted to energy production only,27 the elevated PC flux and OAA pool observed in diabetic mice must have also catered

to the increased FAS demand. This agrees with our recent observation in the hypertrophied heart, in which a larger 13C-citrate signal (from increased pyruvate anaplerosis) was recorded.28 Moreover, detection of citrate pool with hyperpolarized [2-13C]pyruvate substrate Luminespib manufacturer has recently been demonstrated to be feasible in the study of myocardial TCA flux29; therefore, similar measurements in the insulin-resistant liver will undoubtedly aid in validating the hypothesis that an enlarged citrate pool supports FAS. Metformin is used clinically to counter elevated FAS and gluconeogenesis in diabetes, primarily through its activation of adenosine-monophosphate–activated protein kinase.30 In this study, we demonstrated that metformin treatment

leads to reduced HGP by, at least check details in part, decreasing PC activity, as well as production of malate and aspartate from pyruvate. The advent of hyperpolarized 13C MRS has enabled visualization of real-time metabolism in the in vivo mouse liver, in particular, the anaplerosis of pyruvate into the TCA cycle. The distinct patterns in downstream metabolite progression suggest that hyperpolarized 13C MRS is sensitive to subtle differences in metabolic conversions. It is worth noting that LDH-, ALT-, MDH-, and AST-mediated conversions are reversible. Therefore, the appearance of lactate, alanine, malate, aspartate, and OAA peaks resulted from the enzyme-mediated exchange of the hyperpolarized 13C label, in which equilibrium is dependent on the concentrations of both substrate and product, as well as the redox potential. Hence, these metabolite signals reflect the concentration of each metabolite that already exists within the cellular environment and in the plasma, rather than net metabolite production.

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