Grimbert S, Fromenty B, Fisch C, Letteron P, Berson A, Durand-Schneider A M, Feldmann G, Pessayre D
Unité de Recherches de Physiopathologie Hépatique (Institut National de la Santé et de la Recherche Médicale Unité 24, Hôpital Beaujon, Clichy, France.
Hepatology. 1993 Apr;17(4):628-37. doi: 10.1002/hep.1840170417.
Severe impairment of the beta-oxidation of fatty acids, as a consequence of a single factor or a combination of different causes, leads to microvesicular steatosis of the liver. In an effort to understand the mechanism(s) leading to the development of acute fatty liver of pregnancy in some women, we determined the effects of pregnancy on the mitochondrial oxidation of fatty acids in mice. In vivo, the rate of oxidation of the whole fatty-acid chain length was determined by measuring the rate of exhalation of [14C]CO2 after intragastric administration of a tracer dose of [U-14C]palmitic acid. [14C]CO2 exhalation was not significantly decreased at 14 days of gestation, but it had declined by 40% at 18 days of gestation (i.e., 24 to 48 hr before delivery). The rate of first beta-oxidation cycle was assessed by measuring the rate of [14C]CO2 exhalation after administration of [1-14C]octanoic acid, [1-14C]butyric acid or [1-14C]palmitic acid. [14C]CO2 exhalation had declined by 60%, 46%, and 24% after administration of [1-14C]octanoic acid, [1-14C]butyric acid and [1-14C]palmitic acid, respectively, in 18-day-pregnant mice. Total hepatic lipids and triglycerides, expressed per gram of liver, remained unchanged in 18-day-pregnant mice. In vitro, the rate of mitochondrial beta-oxidation (expressed per milligram of protein) had decreased by 47% at 18 days' gestation with [U-14C]palmitic acid as substrate and by 33% with [1-14C]octanoic acid but remained unchanged with [1-14C]palmitic acid. The activity of the tricarboxylic acid cycle, assessed by the formation of [14C]CO2 from [1-14C]acetic acid, had decreased by 24%. We conclude that the mitochondrial oxidation of fatty acids decreased during late-term pregnancy in mice as a consequence of both decreased mitochondrial beta-oxidation of medium-chain fatty acids, and decreased activity of the tricarboxylic acid cycle. We suggest that this effect, in combination with other factors, may contribute to the development of fatty liver of pregnancy in some pregnant women.
由于单一因素或多种不同原因的组合导致脂肪酸β-氧化严重受损，会引发肝脏微泡性脂肪变性。为了了解部分女性妊娠急性脂肪肝发生发展的机制，我们测定了妊娠对小鼠脂肪酸线粒体氧化的影响。在体内，通过胃内给予示踪剂量的[U-14C]棕榈酸后测量[14C]CO2呼出速率，来测定整个脂肪酸链长度的氧化速率。在妊娠14天时，[14C]CO2呼出量没有显著下降，但在妊娠18天时（即分娩前24至48小时）下降了40%。通过测量给予[1-14C]辛酸、[1-14C]丁酸或[1-14C]棕榈酸后[14C]CO2呼出速率，来评估首次β-氧化循环的速率。在妊娠18天的小鼠中，给予[1-14C]辛酸、[1-14C]丁酸和[1-14C]棕榈酸后，[14C]CO2呼出量分别下降了60%、46%和24%。以每克肝脏计算，妊娠18天的小鼠肝脏总脂质和甘油三酯含量保持不变。在体外，以[U-14C]棕榈酸为底物时，妊娠18天时线粒体β-氧化速率（以每毫克蛋白质表示）下降了47%，以[1-14C]辛酸为底物时下降了33%，而以[1-14C]棕榈酸为底物时保持不变。通过[1-14C]乙酸生成[14C]CO2来评估三羧酸循环的活性，其活性下降了24%。我们得出结论，由于中链脂肪酸线粒体β-氧化减少以及三羧酸循环活性降低，小鼠妊娠晚期脂肪酸的线粒体氧化减少。我们认为，这种效应与其他因素共同作用，可能导致部分孕妇发生妊娠脂肪肝。
