DECREASED MITOCHONDRIAL OXIDATION OF FATTY-ACIDS IN PREGNANT MICE - POSSIBLE RELEVANCE TO DEVELOPMENT OF ACUTE FATTY LIVER OF PREGNANCY

Severe impairment of the beta-oxidation of fatty acids, as a consequen ce of a single factor or a combination of different causes, leads to m icrovesicular steatosis of the liver. In an effort to understand the m echanism(s) leading to the development of acute fatty liver of pregnan cy in some women, we determined the effects of pregnancy on the mitoch ondrial oxidation of fatty acids in mice. In vivo, the rate of oxidati on of the whole fatty-acid chain length was determined by measuring th e rate of exhalation of [C-14]CO2 after intragastric administration of a tracer dose of [U-C-14]palmitic acid. [C-14]CO2 exhalation was not significantly decreased at 14 days of gestation, but it had declined b y 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 [C-14]CO2 exhalation after administration of [1-C-14]octanoic acid , [1-C-14]butyric acid or [1-C-14]palmitic acid. [C-14]CO2 exhalation had declined by 60%, 46%, and 24% after administration of [1-C-14]octa noic acid, [1-C-14]butyric acid and [1-C-14]palmitic acid, respectivel y, in 18-day-pregnant mice. Total hepatic lipids and triglycerides, ex pressed per gram of liver, remained unchanged in 18-day-pregnant mice. In vitro, the rate of mitochondrial beta-oxidation (expressed per mil ligram of protein) had decreased by 47% at 18 days' gestation with [U- C-14]palmitic acid as substrate and by 33% with [1-C-14]octanoic acid but remained unchanged with [1-C-14]palmitic acid. The activity of the tricarboxylic acid cycle, assessed by the formation of [C-14]CO2 from [1-C-14]acetic acid, had decreased by 24%. We conclude that the mitoc hondrial oxidation of fatty acids decreased during late-term pregnancy in mice as a consequence of both decreased mitochondrial beta-oxidati on of medium-chain fatty acids, and decreased activity of the tricarbo xylic acid cycle. We suggest that this effect, in combination with oth er factors, may contribute to the development of fatty liver of pregna ncy in some pregnant women.