Targeting
Heart Failure in Obesity and Type 2 Diabetes:
The incidence of obesity and type 2 diabetes is increasing
nationwide at alarming rates in recent years. Type 2 diabetes
is the most common type representing over 90% of all diabetic
patients. It is estimated that about 61 million Americans
are obese (Body Mass Index > 25 kg/m2); about 21 million are
afflicted with type 2 diabetes (hyperglycemia) and another
41 million are estimated to have pre-diabetes (insulin insensitivity).
The diabetes cost to the nation was estimated to be over $175
billion. The incidence of heart failure is also steadily increasing
with the increase in the number of obese and type 2 diabetic
patients. In view of the expected rise in the incidence of
heart failure as these populations age, there is an urgent
need for understanding the molecular and cellular mechanisms
underlying heart failure and for designing rational strategies
for prevention and cure for this looming public health catastrophe
Lipid accumulation in heart cells is the hallmark of failing
hearts in obese and type 2 diabetic patients. Long-chain fatty
acyl-coenzyme and its precursor fatty acyl-carnitine are the
most toxic of the lipid metabolites. Currently, there is no
prevention or treatment of their accumulation and toxic effects
in the heart in obesity and type 2 diabetes. The goal of my
research program is to develop a pharmacological mechanism
that can accelerate the breakdown of fatty acid metabolites
and prevent lipid accumulation and their toxic effects in
the heart. Mitochondrial matrix fatty acyl-coenzyme thioesterase-1
(MTE-1 aka ACOT2), which normally expresses at low levels,
breaks down long-chain fatty acyl-coenzyme to free fatty acid
and free coenzyme (see the figure below). Activation of MTE-1
and acceleration of breakdown and oxidation of acyl-coenzyme
and acyl-carnitine can be an effective pharmacological approach
to prevention and treatment of lipid accumulation and heart
failure in obesity and type 2 diabetes. However, the benefits
of activation of the MTE-1 in the heart are currently unknown.
Also unknown is whether inhibition of MTE-1 due to mutation
of its gene causes accumulation of acyl-coenzyme and acyl-carnitine
in heart cells in obesity and type 2 diabetes. Without this
knowledge, MTE-1 cannot be targeted for pharmacological prevention
or treatment of heart failure in obesity and type 2 diabetes.
To study the risks of inhibition and benefits of activation
of MTE-1, we have generated targeted MTE-1 overexpressed mice
and MTE-1 knockout mice. The rationale of our studies is that
once the benefits of activation and risks of inhibition in
mice are known, MTE-1 can be targeted for drug development
for the purpose of prevention and treatment of heart failure
in obese and type 2 diabetic patients.
The
Novel Long-Chain Free Fatty Acid Generation and Export Pathway
(green arrows) in Heart
Mitochondria.
(Gerber LK, Aronow BJ, & Matlib MA. American Journal of
Physiology, Vol. 291, C1198-C1207, 2006)
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