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Department of Medicine and the Liver Center, University of California, San Francisco, California 94110-0538; and Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Louis University Health Sciences Center, St. Louis, Missouri 63110
Hepatic clearance of
long-chain fatty acids is substantially faster in females than in
males, a fact that may underlie known gender-related differences in
lipoprotein metabolism and associated disease states. To further
investigate the transport steps responsible for this difference, we
used a novel method combining multiple-indicator dilution and
steady-state measurements of palmitate extraction from albumin
solutions. We found that cytoplasmic transport of palmitate is
sufficiently slow (diffusion constants 9.0 and 5.9 × 10
9
cm2/s for male and female liver,
respectively) that the steady-state concentration of palmitate in the
center of the cell should be ~0.5 of that found in the cytoplasm just
beneath the plasma membrane. Previous studies in cultured
liver cells using nonphysiological fatty acids have shown more rapid
cytoplasmic transport in females. This sex difference reflects higher
concentrations of cytosolic fatty acid-binding protein, which acts as a
carrier system to transport fatty acids across cell water layers. The
current study confirmed slow cytoplasmic diffusion rates in intact
perfused rat liver using a physiological fatty acid and found a similar female-to-male ratio. Female liver also had a greater influx rate constant and a larger vascular volume than male liver but had a similar
rate of metabolism. Rapid cytoplasmic diffusion enhances movement of
palmitate into deeper layers of the cell cytoplasm, thus reducing
efflux. The larger sinusoidal volume in females not only permits more
dissociation of palmitate from albumin within the sinusoids but also
may generate a greater permeability-surface area product. These
multiple sex-related differences combine to produce a nearly twofold
greater steady-state uptake rate by female liver.
cytoplasmic transport; diffusion gradients; fatty acid-binding proteins; long-chain fatty acids; sex factors; carrier proteins; membrane transport; multiple-indicator dilution; hepatic uptake; rate constants; mathematical models; kinetics
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