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Volume 04, Issue 01 - January, 2008

Mitochondrial Research Bulletin

Published by:
MitoSciences Inc.
Advancing Vital Discoveries in Mitochondrial Research

Edited by:
Dr. Roderick Capaldi

Written by:
Elisa Oquendo, M.D., D.Phil.
Volume 04, Issue 01 - January 2008
Past Issues of MitoNews can be found at:


In this Issue:

1. Benzafibrate: Candidate Drug for the Treatment of Fatty Acid
Oxidation Disorders

2. HIF1-alpha and Fatty Acid Metabolism

3. Overloading Mitochondria into Insulin Resistance

4. PPAR Agonists in the Treatment of Non-Alcoholic Fatty Liver

5. Fatty Acid Metabolism in the Pathogenesis of Hepatocarcinoma
Due to Chronic Hepatitis C Infection

6. The Players in SCHAD Deficiency

7. Sudden Infant Death Syndrome and Fatty Acid Oxidation

Benzafibrate is a well known fibric acid derivative that has been
used safely for over 25 years in the treatment of hyperlipidemias.
GOBIN-LIMBALLE et al. recently showed that treatment of
VLCAD deficient fibroblasts cultures with 400µM
Benzafibrate, rescues the biochemical defect in a genotype
dependant manner. The authors ranked the genotypes in three
groups according to theresponse levels to benzafibrate. Mapping
of the molecular defects on a three-dimensional model of the
VLCAD protein showed that the responsive phenotypes did not
affect the architecture of the catalytic site nor did they affect the
quaternary structure of the whole enzyme. Analysis of the
phenotype/genotype relationships showed that over 90% of the
responsive cultures had come from patients with the myopathic
form of the disease.

A previous study by DJOUADI et al. also provided evidence that
Bezafibrate could lead to normalization of 3H-palmitate and 3H-
myristate oxidation rates in CPTII deficient cell cultures.
Later studies by the same authors showed that this effect was
dependant on activation PPAR-beta/delta receptors rather than on the
activation of PPAR-alpha receptors. Benzafibrate is currently
considered (as ăpost hocä understanding) the prototype of
clinically tested pan-PPAR ligands. More studies
will be needed to determine whether other FAO disorders could
benefit from Benzafibrate treatment or from specific PPAR-beta/delta
agonists. Nevertheless current data provide the grounds for clinical
studies using benzafibrate to correct VLCAD and CPTII defects.

Gobin-Limballe, S. et al., Am J Hum Genet 81 (6), 1133 (2007).
Djouadi, F. et al., Pediatr Res 54 (4), 446 (2003).
Djouadi, F., Aubey, F., Schlemmer, D., and Bastin, J., J Clin
Endocrinol Metab 90 (3), 1791 (2005).
Cabrero, A. et al., Diabetes 50 (8), 1883 (2001).
Poirier, H. et al., Biochem J 355 (Pt 2), 481 (2001).
Vazquez, M. et al., Mol Cell Biochem 216 (1-2), 71 (2001).
Peters, J. M., Aoyama, T., Burns, A. M., and Gonzalez, F. J.,
Biochim Biophys Acta 1632 (1-3), 80 (2003).

It has been well established that cardiomyocytes adapt to a hypoxic
environment by shifting their ATP production from mitochondrial
fatty acid beta-oxidation to glycolysis. This shift is known to be
mediated by the hypoxia inducible factor or HIF which upregulates
glucose transporters and glycolytic enzymes. Recently a group of
researchers has shown that the role of HIF1-alpha in hypoxic
adaptation goes beyond glycolysis. BELANGER et al showed
that overexpression of HIF1-alpha increases intracellular lipid levels
in neonatal rat cardiomyocytes grown under normoxic conditions.
The lipid accumulation was shown to be associated with a
decrease in CPTI mRNA levels. Although changes in CPTI
mRNA were small under basal conditions, the decrease was highly
significant in the presence of specific PPAR-alpha agonists. These
results suggest that HIF1-alpha not only mediates upregulation of
glycolysis under hypoxic conditions, but also downregulates fatty
acid metabolism by interacting with PPAR-alpha.

Belanger, A. J. et al., Biochem Biophys Res Commun 364 (3), 567 (2007).
Insulin resistance is a condition in which an abnormal high dose of
insulin generates a very small decrease in blood glucose levels. It
is found in most patients with type 2-diabetes and in many patients
with hypertension, cardiovascular disease and obesity. The current
patho-physiological model of insulin resistance proposes that impaired
mitochondrial uptake and oxidation of fatty Acids leads to an abnormal
accumulation of proinflammatory lipid metabolites
(diacylglycerol and ceramides) which activate serine/threonine
kinases and in turn interfere with the insulin signaling pathway.
New evidence published by KOVES et al, has challenged this
widely accepted view of fatty acid oxidation deficiency in insulin
resistance. The authors demonstrated that prolonged lipid
excess, either due to dietetic or genetic manipulation, leads to
increase FAO in rat skeletal muscle and decrease FAO in the liver
during the fasting period. Assessment of FAO was determined by
both acylcarnitine profiling and oleate oxidation measurements.
Furthermore, experimentation leading to suppression of
mitochondrial fatty acid import in skeletal muscle protected
animals against lipid-induced insulin resistance.

The increased FAO in muscle was associated with diminished
levels of TCA cycle intermediates leading to a mitochondrial
impairment in substrate switching during the transition from the
fasting to the fed state. The high rate of FAO in muscle was
attributed to an ăincompleteä oxidation of FA that exceeded the
TCA and ETC flux, with a consequential metabolite accumulation,
mitochondrial stress and insulin resistance.

Koves, T. R. et al., Cell Metab 7 (1), 45 (2008).

Non-alcoholic fatty liver disease (NAFLD) is the most common
liver disorder world-wide. The fast rise in the levels of obesity has
led to a continuous increment in the prevalence of this condition. It
is estimated that 20 ö 35% of the American adult population
suffers from NAFLD and this figure is likely to rise in the next
decade. NAFLD comprises a continuous spectrum of disorders
from hepatic steatosis (abnormal accumulation of fat in
hepatocytes) and steatohepatitis (plus inflammation) to fibrosis and
cirrhosis. Research during the last few years has shown evidence
that NAFLD is in fact a mitochondrial disease. A group at
the Korea University College of Medicine has now demonstrated
in the OLETF rat that both alpha and gamma PPAR agonists
improve biochemical and histological parameters associated with
liver steatosis. Recovery of this condition was assessed after a
prolonged treatment with PPAR agonists (28 weeks) and was
associated to the increased mRNA expression of CPT II, MCAD
and VLCAD.

Pessayre, D. and Fromenty, B., J Hepatol 42 (6), 928 (2005).
Seo, Y. S. et al., J Gastroenterol Hepatol 23 (1), 102 (2008).

Chronic Hepatitis C Virus (HCV) infection can lead to
hepatocarcinogenesis with an approximate 2% annual incidence.
Research has shown that HCV-core protein is perhaps the
responsible oncogenic factor, however the exact mechanism of
tumor development has remained unclear. Recent studies by
TANAKA et al, on HCV-core protein expression in transgenic
(HCVcpTg) mice have shown that the HCV-core tumorogenic
effect is dependent upon the expression levels of PPAR-alpha. The
authors used transgenic mice that were homozygous (Ppara+/+),
heterozygous (Ppara+/-) or null (Ppara--/-) and found that only the
homozygous transgenic mice expressing HCV-core protein
developed hepatic tumors and increased oxidative stress. This
phenotype was surprisingly associated with overexpression of
MCAD. Despite MCAD overexpression, there was an overall
decrease in the oxidation rate of palmitic acid. Results were
further confirmed with the development of hepatic steatosis and
hepatic tumors in Ppara+/-:HCVcpTg after long term Clofibrate
treatment (a PPAR-alpha agonist). The rather paradoxical data was
explained by the dual localization of HCV-core protein in the
nucleus and in mitochondria. HCV-core protein is known to bind and
stabilize PPAR-alpha and hence promotes the influx of fatty
acids from blood. It is also known that localization of the
core protein in mitochondria increases Ca+2 influx, inhibits
Complex I activity and induces ROS production. The
investigators hypothesized that the increased ROS production
could account for the decreased levels of Fatty acid B-oxidation.
This in association with an increased influx of fatty acids into the
cytoplasm (due to stabilization of PPAR-alpha) leads to hepatic
steatosis and hepatocarcinogenesis.

Moriya, K. et al., Nat Med 4 (9), 1065 (1998).
Yu, S. and Reddy, J. K., Biochim Biophys Acta 1771 (8), 936 (2007).
Korenaga, M. et al., J Biol Chem 280 (45), 37481 (2005).
Tanaka, N. et al., J Clin Invest (2008).

The molecular basis for SCHAD deficiency has been the subject of
much controversy and research during the last 12 years.
Heterogeneous biochemical and clinical phenotypes have led to
hypothesize that different enzyme or regulatory factors may be
involved. A Swedish group led by Udo Oppermann has tried to
dissect the causes behind such heterogeneity. Through
immunoblot and sequence analysis carried out in 5 unrelated
patients, the authors found that the HADH1 gene is the only gene
responsible for this disease. Furthermore, a His-tag pull down
experiment led the authors to identify Type 1 glutamate
dehydrogenase as an important interacting partner of SCHAD1
protein (HADH1). The interaction may suggest a possible
regulatory link between B-oxidation, the citric acid cycle and the
urea cycle. Whether such interaction could have an impact in the
biochemical and clinical heterogeneity of SCHAD deficiency is yet
to be determined.

Filling, C. et al., Biochem Biophys Res Commun (2007).

Sudden infant death syndrome (SIDS) is known to occur as a
consequence of fatty acid oxidation deficiency in 1 ö 5% of the
cases. Despite the known link between these two conditions there
is still a lot of controversy about the importance of post-mortem
screening for FAO disorders in SIDS. A recent publication has
shown that screening of subjects with evidence of hepatic steatosis
for MCAD or MTP α-subunit can find mutations in 12.5% of the
cases. The prevalent mutations found were MCAD A985G and
MTP G1528C.

Yang, Z., Lantz, P. E., and Ibdah, J. A., Pediatr Int 49 (6), 883 (2007).

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