A Biochemical Basis for Depressed Ketogenesis in Sepsis

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Abstract
Several investigators have demonstrated a diminished rate of ketogenesis during inflammatory or infectious states despite the availability of free fatty acids supplied to the liver. The biochemical mechanism for this effect is unknown. Malonyl-CoA has been proposed to be a regulator of ketogenesis. Malonyl-CoA levels are low in states of rapid ketogenesis such as starvation or diabetes and high in states of reduced ketogenesis such as carbohydrate feeding. In the present study, the effect of an intra-abdominal abscess on the level of hepatic malonyl-CoA was investigated in four groups of animals (fed control, sterile inflammation, small chronic septic abscess, large chronic septic abscess). Liver samples were frozen in situ 5 days following the intraperitoneal introduction of a rat-fecal agar pellet inoculated with a known bacterial flora which generated an abscess [sterile inflammatory; Bacteroides fragilis 108/ml + Escherichia coli 102/ml (small, 0.8 ml or large, 1.5 ml) abscess pellet]. The level of malonyl-CoA in normal fed rats was 5.0 .+-. 0.6 nmol/gm wet wt (n = 9). The malonyl-CoA level was not altered in animals with a sterile inflammation. However, hepatic malonyl-CoA levels were significantly increased in small (10 + 1 nmole/gm wet wt) (p < 0.05; n = 9) or large (12 .+-. 1 nmol/gm wet wt) (p < 0.01; n = 14) septic abscess rats compared to control fed and sterile inflammatory rats. Hepatic ketone bodies (.beta.-hydroxybutyrate and acetoacetate) did not increase in sepsis over control or sterile inflammation. The level of acetyl-CoA, the precursor for ketone bodies, was 63 .+-. 10 nmole/gm wet wt in control fed (n = 9) and was decreased to 48 .+-. 12 nmol/gm wet wt (p < 0.05; n = 10) in sterile inflammatory animals. The level of hepatic acetyl-CoA was increased over sterile but not control animals in small (62 .+-. 14 nmole/gm wet wt; n = 8) or large (67 .+-. 15 nmole/gm wet wt; n = 14) septic abscess animals. These results are compatible with the hypothesis that inhibition of the carnitine:acyl-CoA transferase I by increased malonyl-CoA may limit the formation of acetyl-CoA from long-chain fatty acids in sepsis. Increased acetyl-CoA levels are required for increased rates of ketogenesis. The increase in malonyl-CoA may differentiate the regulation of ketogenesis in sepsis from that in inflammation and implies an altered hepatic production of fuels in sepsis.