Role of the Liver in Regulation of Ketone Body Production during Sepsis

Abstract

A B S T R A C T During caloric deprivation, the septic host may fail to develop ketonemia as an adaptation to starvation. Because the plasma ketone body concentration is a function of the ratio of hepatic production and peripheral usage, a pneumococcal sepsis model was used in rats to measure the complex metabolic events that could account for this failure, including the effects of infection on lipolysis and esterification in adipose tissue, fatty acid transport in plasma and the rates of hepatic ketogenesis and whole body oxidation of ketones. Some of the studies were repeated with tularemia as the model infection. From these studies, it was concluded that during pneumococcal sepsis, the failure of rats to become ketonemic during caloric deprivation was the result ofreduced ketogenic capacity of the liver and a possibly decreased hepatic supply of fatty acids. The latter appeared to be a secondary consequence of a severe reduction in circulating plasma albumin, the major transport protein for fatty acids, with no effect on the degree of saturation of the albumin with free fatty acids. Also, the infection had no significant effect on the rate of lipolysis or release of fatty acids from adipose tissue. Ketone body usage (oxidation) was either unaffected or reduced during pneumococcal sepsis in rats. Thus, a reduced rate of ketone production in the infected host was primarily responsible for the failure to develop starvation ketonemia under these conditions.

Infection decreases fatty acid oxidation and nuclear hormone receptors in the diaphragm

“…These data suggest that the decrease in these nuclear hormone receptors and their coactivators plays an important role in regulating FA metabolism during infection. In fact, studies have shown that, during sepsis, there is a decrease in FA oxidation in the liver, kidney, and heart ( 24,(27)(28)(29)(30)(31)(32).…”

“…This increase appears to be substrate driven as expression of the enzymes that catalyze the incorporation of FAs into triglycerides is decreased rather than increased. Thus, in the diaphragm, similar to the liver, heart, and kidney, infection induces a decrease in FA oxidation with an increase in FA incorporation into triglycerides ( 24,(27)(28)(29)(30)(31)(32).…”

Adipocyte, Adipose Tissue, and Infectious Disease

“…In animal models, it was demonstrated that E. coli-induced sepsis resulted in a significant decrease in lipoprotein lipase (LPL), leading to a marked decrease in clearance of triglycerides and free fatty acids in cardiac tissue, adipose tissue, and muscle (64,65). This was associated with an increase in de novo hepatic lipogenesis (65,131). The administration of LPS and many cytokines to animals rapidly increased serum triglyceride levels which persisted (65).…”

Beneficial Effects of Enteral Fat Administration on Liver Dysfunction, Liver Lipid Accumulation, and Protein Metabolism in Septic Rats.

“…In general, nonesterified fatty acid concentration in blood decreases during sepsis in man and in experimental animals. Wannemacher et al (19) reported that the decrease could be a consequence of an infection-induced decrease in plasma albumin, which is the fatty acid carrier. The albumin-bound free fatty acids are only one source of oxidizable fatty acid substrates for peripheral tissues (23).…”