High mitochondrial redox potential may promote induction and activation of UCP2 in hepatocytes during hepatothermic therapy

doi:10.1016/j.mehy.2004.01.040

Medical Hypotheses

Volume 64, Issue 6, 2005, Pages 1216-1219

https://doi.org/10.1016/j.mehy.2004.01.040 Get rights and content

Abstract

Although uncoupling protein-1 is a key mediator of thermogenesis in activated brown fat, the more recently characterized uncoupling proteins-2 and -3 do not appear to influence basal metabolism, but rather may function to diminish excessive mitochondrial superoxide production when mitochondrial redox potential is high. Under these circumstances, superoxide within the mitochondrial matrix directly activates uncoupling protein-2 (UCP2), and may also promote induction of this protein. Normal healthy hepatocytes do not express UCP2, but this protein is induced in hepatocytes that are steatotic or that are treated with agents that boost superoxide production. It is proposed that induction and activation of UCP2 may play a role in the thermogenesis evoked by hepatothermic therapy, a strategy designed to decrease body fat by maximizing hepatic fatty acid oxidation. Under these conditions, high mitochondrial redox potential would be expected, and induction of UCP2's uncoupling activity would represent a homeostatically appropriate antioxidant response.

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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High mitochondrial redox potential may promote induction and activation of UCP2 in hepatocytes during hepatothermic therapy

Abstract

Section snippets

Hepatothermic therapy – a strategy for amplifying hepatic fat oxidation

High mitochondrial redox potential may induce UCP2 in hepatocytes

Superoxide directly activates UCP2

Adjunctive measures for inducing UCP2 and proton leak

Med. Hypotheses

Med. Hypotheses

Biochem. Biophys. Res. Commun.

FEBS Lett.

J. Biol. Chem.

Arch. Biochem. Biophys.

Biochem. Biophys. Res. Commun.

Gastroenterology

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.