SEX-DIFFERENCES IN MULTIPLE STEPS IN HEPATIC TRANSPORT OF PALMITATE SUPPORT A BALANCED UPTAKE MECHANISM

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. T o further investigate the transport steps responsible for this differe nce, we used a novel method combining multiple-indicator dilution and steady-state measurements of palmitate extraction from albumin solutio ns. We found that cytoplasmic transport of palmitate is sufficiently s low (diffusion constants 9.0 and 5.9 X 10(-9) cm(2)/s for male and fem ale liver, respectively) that the steady-state concentration of palmit ate in the center of the cell should be similar to 0.5 of that found i n the cytoplasm just beneath the plasma membrane. Previous studies in cultured liver cells using nonphysiological fatty acids have shown mor e 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 la yers. 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 s imilar rate of metabolism. Rapid cytoplasmic diffusion enhances moveme nt of palmitate into deeper layers of the cell cytoplasm, thus reducin g efflux. The larger sinusoidal volume in females not only permits mor e dissociation of palmitate from albumin within the sinusoids but also may generate a greater permeability-surface area product. These multi ple sex-related differences combine to produce a nearly twofold greate r steady-state uptake rate by female liver.