Exposure to the toxins methylene cyclopropyl
acetic acid (
MCPA) and methylene cyclopropyl
glycine (MCPG) of unripe ackee and litchi fruit can lead to
hypoglycemia and death; however, the molecular mechanisms by which
MCPA and MCPG cause
hypoglycemia have not been established in vivo To determine the in vivo mechanisms of action of these toxins, we infused them into conscious rodents and assessed rates of hepatic gluconeogenesis and ketogenesis, hepatic
acyl-CoA and hepatic
acetyl-CoA content, and hepatocellular energy charge. MCPG suppressed rates of hepatic β-oxidation as reflected by reductions in hepatic ketogenesis, reducing both short- and medium-chain hepatic
acyl-CoA concentrations. Hepatic
acetyl-CoA content decreased, and hepatic
glucose production was inhibited.
MCPA also suppressed β-oxidation of short-chain acyl-CoAs, rapidly inhibiting hepatic ketogenesis and hepatic
glucose production, depleting hepatic
acetyl-CoA content and
ATP content, while increasing other short-chain acyl-CoAs. Utilizing a recently developed positional isotopomer NMR tracer analysis method, we demonstrated that
MCPA-induced reductions in hepatic
acetyl-CoA content were associated with a marked reduction of hepatic
pyruvate carboxylase (PC) flux. Taken together, these data reveal the in vivo mechanisms of action of
MCPA and MCPG: the
hypoglycemia associated with ingestion of these toxins can be ascribed mostly to
MCPA- or MCPG-induced reductions in hepatic PC flux due to inhibition of β-oxidation of short-chain acyl-CoAs by
MCPA or inhibition of both short- and medium-chain acyl-CoAs by MCPG with resultant reductions in hepatic
acetyl-CoA content, with an additional contribution to
hypoglycemia through reduced hepatic
ATP stores by
MCPA.