Sex differences in multiple steps in hepatic transport of palmitate support a balanced uptake mechanism

Luxon, Bruce A.; Hollý, D; Milliano, Michael T.; Weisiger, Richard A.

doi:10.1152/ajpgi.1998.274.1.g52

Cited by 20 publications

(21 citation statements)

References 27 publications

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“…The first is the long-recognized difference in long chain fatty acid uptake and utilization in the livers of male and female rats (Ockner et al, 1979). There is no explanation of this difference that is wholly satisfactory, either in terms of the known plasma membrane fatty acid binding protein (FABPpm) or cytosolic fatty acid binding protein (Luxon et al, 1998;Sorrentino et al, 1992). The second is the difference between men and premenopausal women with respect to both blood cholesterol levels and the incidence of cholesterol-associated diseases (Anderson et al, 1987;Barker et al, 1979;Simons, 1986).…”

Section: Zhang Et Almentioning

confidence: 99%

CD36/Fatty Acid Translocase in Rats: Distribution, Isolation from Hepatocytes, and Comparison with the Scavenger Receptor SR-B1

Zhang

Fitzsimmons

Cleland

et al. 2003

Laboratory Investigation

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SUMMARY:The new mAb UA009 recognizes an antigen expressed by microvascular endothelium, by lymphatic endothelium, and by some epithelia in a number of organs, including the small intestine, lactating mammary gland, kidney, lung, sebaceous glands, and circumvallate papillae of the tongue. This antigen is also expressed abundantly in the splenic red pulp and marginal zone and by monocytes, macrophages, and erythrocytes (but not by platelets). Among tissues that store or metabolize fatty acids, the antigen is expressed by adipocytes, cardiomyocytes, and red skeletal muscle. Importantly, it is expressed by steroidogenic cells in the adrenal gland, testis, and ovary, whereas in the liver it is expressed by hepatocytes in a pattern that is dependent on gender and genetic background. mAb UA009 immunoprecipitated a mol wt 85-kDa surface protein from detergent extracts of hepatocytes from Dark Agouti female rats. The N-terminal amino acid sequence of this protein was identical to fatty acid translocase (FAT), the rat cluster of differentiation 36 (CD36) ortholog. The mAb also reacted with COS-7 cells transfected with cDNA encoding FAT. cDNAs encoding a CD36/FAT-like polypeptide were prepared from both liver and heart RNA by RT-PCR. The nucleotide sequences obtained from these cDNAs (Dark Agouti rats) revealed identity and 99% similarity, respectively, with the published sequences of Cd36/Fat in rats of the Wistar and Sprague-Dawley strains. The absence of the UA009 antigen in CD36/FAT-deficient SHR/N rats confirmed the identity of the UA009 antigen and CD36/FAT. We suggest that CD36/FAT might function in the liver as a sex-regulated accessory molecule, either in reverse cholesterol transport and/or in fatty acid uptake. (Lab Invest 2003, 83:317-332).

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Section: Zhang Et Almentioning

confidence: 99%

CD36/Fatty Acid Translocase in Rats: Distribution, Isolation from Hepatocytes, and Comparison with the Scavenger Receptor SR-B1

Zhang

Fitzsimmons

Cleland

et al. 2003

Laboratory Investigation

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“…L-FABP levels are known to be gender dependent, with females showing higher levels than males (25). L-FABP is also altered in various conditions, such as pregnancy and clofibrate treatment (6,26,31).…”

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confidence: 99%

Fatty acid binding protein is a major determinant of hepatic pharmacokinetics of palmitate and its metabolites

Hung

Burczynski

Chang

et al. 2003

American Journal of Physiology-Gastrointestinal and Liver Physi

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kinetics of [ 3 H]palmitate and its low-molecular-weight metabolites in perfused rat livers were studied using the multiple-indicator dilution technique, a selective assay for [ 3 H]palmitate and its low-molecular-weight metabolites, and several physiologically based pharmacokinetic models. The level of liver fatty acid binding protein (L-FABP), other intrahepatic binding proteins (microsomal protein, albumin, and glutathione S-transferase) and the outflow profiles of [ 3 H]palmitate and metabolites were measured in four experimental groups of rats: 1) males; 2) clofibrate-treated males; 3) females; and 4) pregnant females. A slow-diffusion/bound model was found to better describe the hepatic disposition of unchanged [3 H]palmitate than other pharmacokinetic models. The L-FABP levels followed the order: pregnant female Ͼ clofibrate-treated male Ͼ female Ͼ male. Levels of other intrahepatic proteins did not differ significantly. The hepatic extraction ratio and mean transit time for unchanged palmitate, as well as the production of low-molecular-weight metabolites of palmitate and their retention in the liver, increased with increasing L-FABP levels. Palmitate metabolic clearance, permeability-surface area product, retention of palmitate by the liver, and cytoplasmic diffusion constant for unchanged [3 H]palmitate also increased with increasing L-FABP levels. It is concluded that the variability in hepatic pharmacokinetics of unchanged [ 3 H]palmitate and its lowmolecular-weight metabolites in perfused rat livers is related to levels of L-FABP and not those of other intrahepatic proteins.clofibrate; pregnancy; multiple indicator dilution; hepatic extraction ratio; cytoplasmic diffusion constant NONESTERIFIED, LONG-CHAIN fatty acids (hereafter referred to as fatty acids) play a vital role in many cellular processes. They are an important source for cellular energy and form the building blocks from which various cellular components are synthesized. Some fatty acids are precursors for biological mediators, whereas others may interact with the cell membrane to regulate various cellular functions. Uptake of fatty acids has been shown to parallel the level of liver fatty acid binding protein (L-FABP) (22).L-FABP levels are known to be gender dependent, with females showing higher levels than males (25). L-FABP is also altered in various conditions, such as pregnancy and clofibrate treatment (6,26,31). Although the variation in the content of various intrahepatic proteins in liver disease has been used to account for the uptake, binding, and metabolism of solutes (20), the influence of intrahepatic proteins other than L-FABP [e.g., microsomal protein (MP), cytochrome P-450 (CYP), albumin (Alb), and glutathione S-transferase (GST)] on the hepatic disposition of [ 3 H]palmitate has been studied to a limited extent. Most studies investigating the fatty acid uptake into the liver have used isolated hepatocytes with some studies using intact livers (26,38).In this work, we examined the relationship between the hepatic pharma...

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“…For example, liver cells contain Ͼ10 m 2 of membranes per cubic centimeter of volume (4), sufficient to bind the vast majority of unesterified fatty acid molecules in the cytoplasm (20). Yet, hepatocytes efficiently transfer fatty acids from the plasma membrane to intracellular sites of metabolism (16,20).…”

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confidence: 99%

“…More than 20 years ago, Tipping and Ketterer (32) proposed that soluble binding proteins may stim-ulate cytoplasmic transport of their ligands by increasing their aqueous solubility. FABP has been shown to stimulate intracellular fatty acid mobility in cultured cells (18,20,22,23), perfused rat liver (16,19), and artificial cytoplasm (29,38), whereas knock out of the gene for heart FABP was found to greatly impair cardiac fatty acid metabolism (3). Weisiger and co-workers (15,16,20) have shown that the rate of fatty acid diffusion within liver cells is directly proportional to the concentration of liver FABP, and they have proposed that soluble binding proteins act as an aqueous carrier system that reduces binding of fatty acids and other molecules to immobile cytoplasmic membranes (20,37).…”

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confidence: 99%

“…FABP has been shown to stimulate intracellular fatty acid mobility in cultured cells (18,20,22,23), perfused rat liver (16,19), and artificial cytoplasm (29,38), whereas knock out of the gene for heart FABP was found to greatly impair cardiac fatty acid metabolism (3). Weisiger and co-workers (15,16,20) have shown that the rate of fatty acid diffusion within liver cells is directly proportional to the concentration of liver FABP, and they have proposed that soluble binding proteins act as an aqueous carrier system that reduces binding of fatty acids and other molecules to immobile cytoplasmic membranes (20,37). On the other hand, Zucker and co-workers (41,43) found a decreased rate of fatty acid transfer between vesicles in the presence of a membrane-inactive binding protein (liver FABP), although a membraneactive binding protein (intestinal FABP) stimulated transfer under similar conditions (41).…”

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confidence: 99%

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Transfer of fatty acids between intracellular membranes: roles of soluble binding proteins, distance, and time

Weisiger

Zucker

2002

American Journal of Physiology-Gastrointestinal and Liver Physi

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Soluble fatty acid binding proteins (FABPs) are thought to facilitate exchange of fatty acids between intracellular membranes. Although many FABP variants have been described, they fall into two general classes. "Membrane-active" FABPs exchange fatty acids with membranes during transient collisions with the membrane surface, whereas "membrane-inactive" FABPs do not. We used modeling of fatty acid transport between two planar membranes to examine the hypothesis that these two classes catalyze different steps in intracellular fatty acid transport. In the absence of FABP, the steady-state flux of fatty acid from the donor to the acceptor membrane depends on membrane separation distance (d) approaching a maximum value (J max) as d approaches zero. Jmax is one-half the rate of dissociation of fatty acid from the donor membrane, indicating that newly dissociated fatty acid has a 50% chance of successfully reaching the acceptor membrane before rebinding to the donor membrane. For larger membrane separations, successful transfer becomes less likely as diffusional concentration gradients develop. The mean diffusional excursion of the fatty acid into the water phase (d m) defines this transition. For dϽ Ͻd m, dissociation from the membrane is rate limiting, whereas for dϾ Ͼd m, aqueous diffusion is rate limiting. All forms of FABP increase d m by reducing the rate of rebinding to the donor membrane, thus maintaining J max over larger membrane separations. Membrane-active FABPs further increase J max by catalyzing the rate of dissociation of fatty acids from the donor membrane, although frequent membrane interactions would be expected to reduce their diffusional mobility through a membrane-rich cytoplasm. Individual FABPs may have evolved to match the membrane separations and densities found in specific cell lines.

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Sex differences in multiple steps in hepatic transport of palmitate support a balanced uptake mechanism

Cited by 20 publications

References 27 publications

CD36/Fatty Acid Translocase in Rats: Distribution, Isolation from Hepatocytes, and Comparison with the Scavenger Receptor SR-B1

CD36/Fatty Acid Translocase in Rats: Distribution, Isolation from Hepatocytes, and Comparison with the Scavenger Receptor SR-B1

Fatty acid binding protein is a major determinant of hepatic pharmacokinetics of palmitate and its metabolites

Transfer of fatty acids between intracellular membranes: roles of soluble binding proteins, distance, and time

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