IRIG: Lipotoxicity = Mitochondria + ROS
01/13/2008 08:29
Two studies in recent issues of “Cell Metabolism” and
“Cell ” suggest that overloading of mitochondria with
fatty acids drives oxidative phosphorylation out of
control in mitochondria, leading to incomplete
metabolism of fatty acids and overproduction of ROS
(reactive oxygen species). Prevention of lipid abuse
of oxidative phosphorylation by gene knockout
protected the mice from insulin resistance in dietary
obese mice. The two studies suggest that lipotoxicity
is a result of ROS production from lipid overloading
in mitochondria.
In the first study, fatty acid oxidation in mitochondrial was found to be increased in skeletal muscle of dietary obese mice. However, the increase did not bring in benefit, but incomplete oxidation of fatty acids. The abused mitochondria produced large amount of ROS in oxidation of overloaded fatty acids. It is proposed that ROS leads to insulin resistance in cells loaded with fatty acids. These conclusions are supported by data from metabolomic analysis of tricarboxylic acid cycle products in mitochondria. This paper is recommended by Dr. Eric Ravussin at Pennington (See attachment 1).
In the second study in “Cell”, mitochondrial oxidative phosphorylation is reduced by deletion of AIF (apoptosis inducing factor) gene. Tissue-specific deletion of AIF in muscle or liver generated mitochondrial deficiency in oxidative phosphorylation in the two organs. This engineered mitochondrial “dysfunction” did not produce extra ROS in the presence of lipid overloading. The knockout mice gained weight at normal rate on high fat diet, but did not develop insulin resistance (See attachment 2). This study provides a nice support to the first study about role of mitochondrial ROS in lipid-induced insulin resistance.
By Jianping
---------------------------------------------
Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225)763-3163
E-mail: yej@pbrc.edu
Webpage: http://labs.pbrc.edu/generegulation/index.htm
In the first study, fatty acid oxidation in mitochondrial was found to be increased in skeletal muscle of dietary obese mice. However, the increase did not bring in benefit, but incomplete oxidation of fatty acids. The abused mitochondria produced large amount of ROS in oxidation of overloaded fatty acids. It is proposed that ROS leads to insulin resistance in cells loaded with fatty acids. These conclusions are supported by data from metabolomic analysis of tricarboxylic acid cycle products in mitochondria. This paper is recommended by Dr. Eric Ravussin at Pennington (See attachment 1).
In the second study in “Cell”, mitochondrial oxidative phosphorylation is reduced by deletion of AIF (apoptosis inducing factor) gene. Tissue-specific deletion of AIF in muscle or liver generated mitochondrial deficiency in oxidative phosphorylation in the two organs. This engineered mitochondrial “dysfunction” did not produce extra ROS in the presence of lipid overloading. The knockout mice gained weight at normal rate on high fat diet, but did not develop insulin resistance (See attachment 2). This study provides a nice support to the first study about role of mitochondrial ROS in lipid-induced insulin resistance.
By Jianping
---------------------------------------------
Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225)763-3163
E-mail: yej@pbrc.edu
Webpage: http://labs.pbrc.edu/generegulation/index.htm
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