Ockner R K, Lysenko N, Manning J A, Monroe S E, Burnett D A
J Clin Invest. 1980 May;65(5):1013-23. doi: 10.1172/JCI109753.
The mechanism by which sex steroids influence very low density hepatic lipoprotein triglyceride production has not been fully elucidated. In previous studies we showed that [(14)C]oleate utilization and incorporation into triglycerides were greater in hepatocyte suspensions from adult female rats than from males. The sex differences were not related to activities of the enzymes of triglyceride biosynthesis, whereas fatty acid binding protein (FABP) concentration in liver cytosol was greater in females. These findings suggested that sex differences in lipoprotein could reflect a sex steroid influence on the availability of fatty acids for hepatocellular triglyceride biosynthesis. In the present studies, sex steroid effects on hepatocyte [(14)C]oleate utilization and FABP concentration were investigated directly. Hepatocytes from immature (30-d-old) rats exhibited no sex differences in [(14)C]oleate utilization. With maturation, total [(14)C]oleate utilization and triglyceride biosynthesis increased moderately in female cells and decreased markedly in male cells; the profound sex differences in adults were maximal by age 60 d. Fatty acid oxidation was little affected. Rats were castrated at age 30 d, and received estradiol, testosterone, or no hormone until age 60 d, when hepatocyte [(14)C]oleate utilization was studied. Castration virtually eliminated maturational changes and blunted the sex differences in adults. Estradiol or testosterone largely reproduced the appropriate adult pattern of [(14)C]oleate utilization regardless of the genotypic sex of the treated animal. In immature females and males, total cytosolic FABP concentrations were similar. In 60-d-old animals, there was a striking correlation among all groups (females, males, castrates, and hormone-treated) between mean cytosolic FABP concentration on the one hand, and mean total [(14)C]oleate utilization (r = 0.91) and incorporation into triglycerides (r = 0.94) on the other. In 30-d-old animals rates of [(14)C]oleate utilization were greater, relative to FABP concentrations, than in 60-d-old animals. The sex differences that characterize fatty acid utilization in adult rat hepatocytes are not present in cells from immature animals, and reflect in part the influence of sex steroids. It remains to be determined whether the observed relationship of hepatic FABP concentration to [(14)C]oleate utilization in adult cells is causal or secondary to changes in cellular fatty acid uptake effected through another mechanism. In either case, modulation of triglyceride-rich lipoprotein production by six steroids appears to be mediated to a significant extent by their effects on hepatic fatty acid utilization.
性类固醇影响肝脏极低密度脂蛋白甘油三酯生成的机制尚未完全阐明。在先前的研究中，我们发现成年雌性大鼠肝细胞悬液中[（14）C]油酸的利用率以及其掺入甘油三酯的量均高于雄性大鼠。这种性别差异与甘油三酯生物合成酶的活性无关，而雌性大鼠肝细胞质中脂肪酸结合蛋白（FABP）的浓度更高。这些发现表明，脂蛋白的性别差异可能反映了性类固醇对肝细胞甘油三酯生物合成中脂肪酸可用性的影响。在本研究中，我们直接研究性类固醇对肝细胞[（14）C]油酸利用率和FABP浓度的影响。未成熟（30日龄）大鼠的肝细胞在[（14）C]油酸利用率方面没有性别差异。随着成熟，雌性细胞中总的[（14）C]油酸利用率和甘油三酯生物合成适度增加，而雄性细胞中则显著下降；成年大鼠中明显的性别差异在60日龄时达到最大。脂肪酸氧化几乎没有受到影响。在30日龄时对大鼠进行阉割，并在60日龄时研究肝细胞[（14）C]油酸利用率之前，分别给予雌二醇、睾酮或不给予激素。阉割实际上消除了成熟变化，并减弱了成年大鼠中的性别差异。无论治疗动物的基因型性别如何，雌二醇或睾酮在很大程度上重现了成年大鼠[（14）C]油酸利用率的适当模式。在未成熟的雌性和雄性大鼠中，总的细胞质FABP浓度相似。在60日龄的动物中，所有组（雌性、雄性、阉割大鼠和激素处理组）的平均细胞质FABP浓度一方面与平均总的[（14）C]油酸利用率（r = 0.91）和掺入甘油三酯的量（r = 0.94）另一方面之间存在显著相关性。在30日龄的动物中，相对于FABP浓度，[（14）C]油酸的利用率比60日龄的动物更高。成年大鼠肝细胞中脂肪酸利用的性别差异在未成熟动物的细胞中不存在，并且部分反映了性类固醇的影响。成年细胞中观察到的肝脏FABP浓度与[（14）C]油酸利用率之间的关系是因果关系还是通过另一种机制影响细胞脂肪酸摄取变化的继发结果，仍有待确定。无论哪种情况，性类固醇对富含甘油三酯脂蛋白生成的调节似乎在很大程度上是通过它们对肝脏脂肪酸利用的影响来介导的。
