Jan 2008
IRIG: Autophagy in Metabolic Syndrome
01/13/2008 08:38
In the current issue of “Cell”, there is a very nice
review article on “Autophagy”. The role of autophagy
in metabolic syndrome, longevity, and various
diseases are covered in the review. What is
“Autophagy”? In the introduction, it states that “One
of the most evolutionarily conserved cellular
responses to organismal fasting is the activation of
the lysosomal degradation pathway of autophagy, a
process in which the cell self-digests its own
components. This self-digestion not only provides
nutrients to maintain vital cellular functions during
fasting but also can rid the cell of superfluous or
damaged organelles, misfolded proteins, and invading
microorganisms. Interestingly, self-digestion by
autophagy—a process that is potently triggered by
fasting—is now emerging as a central biological
pathway that functions to promote health and
longevity.”
Attached is the PDF
file.
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
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
|
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
IRIG: Why TZD increases rate of bone fractures in diabetic individuals ?
01/13/2008 08:23
TZD is a well-established insulin sensitizer that is
widely used in clinics for the treatment of type 2
diabetes. Among the major side effects of TZD,
increased rate for bone fractures has been known
together with the side effects of TZD on CDV system.
The molecular mechanism underlying the TZD-associated
fracture is not clear. One possibility is that
activation of PPARg by TZD inhibits the
differentiation of osteoblasts that are required for
bone formation. PPARg is known to inhibit
differentiation of stem cells into osteoblasts and at
meantime promotes differentiation of the stem cells
into adipocytes. In response to PPARg activation,
loss of esteoblasts will lead to less formation of
bone materials, and thus bone fracture. However, this
possibility is challenged by a study in “Nature
Medicine”, in which an increase in bone absorption
was found to be the reason for TZD-associated
fracture. This point is demonstrated using
tissue-specific PPARg knockout mice in which PPARg is
removed in both endothelial cells and osteoclasts.
Osteoclasts are bone-resorbing cells derived from
hematopoietic precursors of the monocyte-macrophage
lineage. The PPARg-KO made the bone density much
higher in the transgenic mice as bone-resorbtion was
inhibited in the bone. This is a result of loss of
osteoclasts. The study reveals that PPARg is required
for osteoclast differentiation from the bone marrow
cells. With normal PPARg expression in osteoblasts,
the KO mice does not loss bone mass in response to
TZD.
Attached is the PDF file of this
paper.
Merry Christmas!
By Jianping at PBRC
------------------------------------------------------
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
Merry Christmas!
By Jianping at PBRC
------------------------------------------------------
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