Fructose and the metabolic syndrome
many investigators have implicated fructose in the
pathogenesis of the metabolic syndrome
40,98–105
and
naFlD.
39,106,107
the liver is the principal site of fructose
metabolism, as it possesses the fructose*specific Glut5
transporter.
108
although adipocytes possess Glut*5
mrna and protein, the level of this transporter in adipose
tissue is quite low.
109
the kidney and small intestine also
possess Glut*5 transporters, but their function is to
transport fructose molecules across their lumena, either
for urinary excretion (to eliminate any systemic fructose
that escapes hepatic clearance) or for release into the
portal circulation, which passes directly to the liver. the
hepatic metabolism of fructose is very different to that
of glucose in that it is insulin independent, bypasses the
process of glycolysis, and increases de novo lipogenesis
to a greater extent. indeed, the hepatic metabolism of
fructose is more reminiscent of that of ethanol.
110
similar
to ethanol, fructose can induce each of the phenomena
associated with the metabolic syndrome (Figure 2).
hypertension
Fructose is phosphorylated by fructokinase, which uses
atP as the phosphate donor, depleting the hepatocyte of
intracellular atP. the scavenger enzyme amP deami*
nase 1 reclaims additional phosphates from aDP, and
in the process generates the waste product uric acid.
uric acid acts within vascular smooth muscle to inhibit
endothelial nitric oxide synthase and resultant nitric
oxide production, which promotes hypertension.
100
our group has shown that sugar*sweetened beverage
consumption positively correlates with uric acid and
blood pressure levels in children,
111
while others have
documented this association in adults.
112
Furthermore,
the uric acid inhibitor allopurinol can reduce blood
pressure in adolescents
113
and adults with obesity.
114
hepatic steatosis
owing to the excess substrate load, excess mitochondrial
acetyl*Coa is formed, exceeding the ability of the tri*
carboxylic acid (tCa) cycle to metabolize it. the excess
acetyl*Coa is converted to citrate, exits into the cytosol via
the citrate shuttle, and serves as the substrate for de novo
lipogenesis. acetyl*Coa dimerizes and is decarboxy*
lated to form malonyl*Coa, which inhibits mitochon*
drial β*oxidation. triglycerides newly formed by de novo
lipogenesis
115
can overwhelm the lipid export machin*
ery and precipitate in the liver, forming intrahepatic
lipid and leading to hepatic steatosis.
hepatic insulin resistance
Fructose*1*phosphate activates dual*specificity mitogen*
activated protein kinase kinase 7 (mKK7),
116
which
stimulates the hepatic enzyme mitogen*activated protein
kinase 8 (maPK8).
117
this kinase is thought to be the
bridge between hepatic metabolism and inflamma*
tion.
118
Furthermore, the intermediate diacylglycerol,
which accumulates during de novo lipogenesis acti*
vates hepatic protein kinase C ε type (PKCε).
119
Both
maPK8 and PKCε trigger serine phosphorylation and
subsequent inactivation of irs*1, which leads to hepatic
insulin resistance.
120–123
Dyslipidemia and muscle insulin resistance
Free fatty acids are also formed, which, when packaged as
triglycerides into heavily fat*laden vlDls, are cleared with
low efficiency, causing dyslipidemia and augmenting the
risk of cardiovascular disease.
115,124
excess circulating lipid
is also taken up by skeletal muscle to form intramyocellular
lipid, which leads to muscle insulin resistance.
125,126
