High mitochondrial redox potential may promote induction and activation of UCP2 in hepatocytes during hepatothermic therapy
Section snippets
Hepatothermic therapy – a strategy for amplifying hepatic fat oxidation
A surprisingly rapid loss of body fat has been noted in overweight patients supplemented during postabsorptive metabolism with adequate doses of hydroxycitrate, carnitine, and pyruvate salts, as an adjuvant to exercise training and low-fat eating advice [1], [2]. The intent of this supplementation regimen is to optimize fat oxidation in hepatic mitochondria by disinhibiting/activating carnitine palmitoyl transferase (with hydroxycitrate and carnitine, administered while insulin is at fasting
High mitochondrial redox potential may induce UCP2 in hepatocytes
Although UCP2 is expressed in healthy livers, this expression is largely confined to Kuppfer cells – production of UCP2 by hepatocytes is minimal [4], [5]. However, UCP2 is expressed in the hepatocytes of obese animals experiencing hepatic steatosis [6], [7]. This may be of functional significance, since, at any given proton motive force across the mitochondrial inner membrane, electron leak was found to be greater in hepatic mitochondria derived from obese animals. Why UCP2 is induced in
Superoxide directly activates UCP2
These findings are consistent with the thesis that the high redox potential in hepatocyte mitochondria during HT can lead to a compensatory induction of UCP2 – possibly owing to increased mitochondrial superoxide generation. Not unlikely, additional mechanism will promote increased mitochondrial electron leak under these circumstances. The rate of this leak increases as a function of electron motive force across the mitochondrial inner membrane, and this function increases steeply as very high
Adjunctive measures for inducing UCP2 and proton leak
There may be various adjunctive measures which could increase mitochondrial proton leak in the context of HT. When rats are treated with the “ergosteroid” 7-keto-DHEA, their hepatocyte mitochondria show increased state 4 proton leak [20], [21]. This agent, which suppresses fat gain in rats, has various thyromimetic effects which appear to be hepato-specific. PPAR-α agonists, such as the fibrate drugs, induce expression of UCP2 in rodent hepatocytes [11], [22]; whether they do so in humans is
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2017, Trends in Food Science and TechnologyCitation Excerpt :Capsaicin-mediated induction of TRPV1 also triggered PPARβ/δ activation, likely leading to downstream induction of UCP2 (Li et al., 2013; McCarty et al., 2015). UCP2 induction increased uncoupling in mitochondria, thus improving the efficiency of hepatic FFA oxidation (McCarty, 2005). Induction of UCP2 in hepatocytes may have potential as an adjuvant to weight control strategies, which attempt to optimize hunger control, selective fat oxidation and thermogenesis by improving the efficiency of hepatic FFA oxidation.
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2014, Journal of Lipid ResearchCitation Excerpt :While the HFD did not affect PDK4 expression, PDK4 mRNA was significantly induced 2.5- and 6-fold, respectively, in LFD- and HFD-fed mice infected with Ad-Elovl5. The HFD had no significant effect on the expression of enzymes involved in fatty acyl carnitine metabolism [carnitine palmitoyl transferase (CPT) 1a and CPT2], mitochondrial β-oxidation [long-chain acyl-CoA dehydrogenase (LCAD), medium-chain acyl-CoA dehydrogenase (MCAD), and short-chain acyl-CoA dehydrogenase (SCAD)], or sirtuin 3 (SIRT3), an NAD+-regulated deacetylase implicated in the control of FAO (25, 33–47) (Fig. 3B). Increased Elovl5 activity, however, significantly (∼2-fold) increased CPT2, LCAD, and MCAD in livers of obese mice.
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2011, Medical HypothesesCitation Excerpt :Moreover, by activating glycine-gated chloride channels in Kupffer cells, glycine exerts anti-inflammatory effects that are highly protective in alcohol-fed rats [68–70]; conceivably, glycine might also blunt the contribution of Kupffer cells to the production of cytokines such as TNF-alpha that exacerbate NAFLD [71]. However, by maximizing hepatic mitochondrial fatty acid oxidation and hence increasing the rate of mitochondrial NADH generation, this strategy runs the risk of further boosting the rate of superoxide production by functionally impaired mitochondria, and thus at least temporarily exacerbating hepatic oxidative stress [72]. Indeed, this phenomenon may explain why prolonged fasting in obese subjects is sometimes accompanied by moderate elevations in serum transaminases [73–75].
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