Decreased mitochondrial oxidation of fatty acids in pregnant mice: Possible relevance to development of acute fatty liver of pregnancy

Abstract

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.

Acute onset lactic acidosis and pancreatitis in the third trimester of pregnancy in HIV-1 positive women taking antiretroviral medication

“…5 It has also been suggested that pregnancy may be associated with low levels of riboflavin and this may potentiate the development of mitochondrial toxicity caused by nucleoside analogues. 6 Riboflavin is a precursor for the flavoprotein co-factors required for oxidative phosphorylation and the production of ATP.…”

Decreased nuclear hormone receptor expression in the livers of mice in late pregnancy

“…Moreover, triglyceride synthesis is decreased in adipose tissue, whereas lipolysis is enhanced during pregnancy (18), resulting in an increase in serum free fatty acid levels. In the liver, pregnancy leads to a reduction in fatty acid oxidation (15), although fatty acid synthesis is increased (62). The increase in de novo fatty acid synthesis and the enhanced delivery of fatty acids from adipose tissue coupled with the decrease in fatty acid oxidation increase the pool of fatty acids available in the liver, resulting in an increase in triglyceride synthesis (58).…”

Troglitazone and liver injury

“…They may reflect adaptive changes because they also occurred after estrogen/progesterone treatment or pregnancy in rats, associated with decreased mitochondrial oxidation. 138,139 Thus, pathological liver apoptosis in patients treated with TGZ does not seem to be a key mechanism for TGZ-induced liver injury.…”