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

Respiratory failure is a major cause of mortality during septic shock and is due in part to decreased ventilatory muscle contraction. Ventilatory muscles have high energy demands; fatty acid (FA) oxidation is an important source of ATP. FA oxidation is regulated by nuclear hormone receptors; studies have shown that the expression of these receptors is decreased in liver, heart, and kidney during sepsis. Here, we demonstrate that lipopolysaccharide (LPS) decreases FA oxidation and the expression of lipoprotein lipase (LPL), FA transport protein 1 (FATP-1), CD36, carnitine palmitoyltransferase beta, medium chain acyl-CoA dehydrogenase (MCAD), and acyl-CoA synthetase, key proteins required for FA uptake and oxidation, in the diaphragm. LPS also decreased mRNA levels of PPARα and β/δ, RXRα, β, and γ, thyroid hormone receptor α and β, and estrogen related receptor alpha (ERRα) and their coactivators PGC-1α, PGC-1β, SRC1, SRC2, Lipin 1, and CBP. Zymosan resulted in similar changes in the diaphragm. Finally, in PPARα deficient mice, baseline CPT-1β and FATP-1 levels were markedly decreased and were not further reduced by LPS suggesting that a decrease in the PPARα signaling pathway plays an important role in inducing some of these changes. The decrease in FA oxidation in the diaphragm may be detrimental, leading to decreased diaphragm contraction and an increased risk of respiratory failure during sepsis.     

Suppression of DHEA sulfotransferase (Sult2A1) during the acute-phase response

The acute-phase response (APR) induces alterations in lipid metabolism, and our data suggest that this is associated with suppression of type II nuclear hormone receptors that are key regulators of fatty acid, cholesterol, and bile acid metabolism. Recently, the farnesoid X receptor (FXR), constitutive androstane receptor (CAR), and pregnane X receptor (PXR) were found to regulate DHEA sulfotransferase (Sult2A1), which plays an important role in DHEA sulfation and detoxification of bile acids. Because FXR, PXR, and CAR are suppressed during the APR, we hypothesized that Sult2A1 is downregulated during the APR. To induce the APR, mice were treated with LPS, which will then trigger the release of various cytokines, and the mRNA levels of Sult2A1 and the sulfate donor 3'-phosphoadenosine 5'-phosphosulfate synthase 2 (PAPSS2), as well as the enzyme activity of Sult2A1, were determined in the liver. We found that mRNA levels of Sult2A1 decrease in a time- and dose-dependent manner during the LPS-induced APR. Similar changes were observed in the mRNA levels of PAPSS2, the major synthase of PAPS in the liver. Moreover, hepatic Sult2A1 activity and serum levels of DHEA-sulfate (DHEA-S) were significantly decreased in LPS-treated animals. These results suggest that decreased levels or activities of FXR, PXR, and CAR during the APR could contribute to decreases in Sult2A1, resulting in decreased sulfation of DHEA and lower circulating level of DHEA-S. Finally, we found that both TNF and IL-1 caused a significant decrease in the mRNA level of Sult2A1 in Hep3B human hepatoma cells, suggesting that the proinflammatory cytokines TNF and IL-1 mediate the inhibitory effect of LPS on Sult2A1 mRNA level. Our study provides a possible mechanism by which infection and inflammation are associated with altered steroid metabolism and cholestasis.     

Down-regulation of liver and heart specific fatty acid binding proteins by endotoxin and cytokines in vivo.

Fatty acid binding proteins (FABPs) are abundantly present in tissues that actively metabolize fatty acids (FA). While their precise physiological function is not known, FABPs have been shown to play a role in the uptake and/or utilization of FA within the cell. FA metabolism is markedly altered during the host response to infection and inflammation. Previous studies have demonstrated that endotoxin or bacterial lipopolysaccharide (LPS) enhances hepatic FA synthesis and re-esterification while inhibiting FA oxidation in liver, heart and muscle. Now, we have examined the in vivo effects of LPS and cytokines on FABPs in liver (L-FABP), heart and muscle (H-FABP). Syrian hamsters were injected with LPS, tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) and the mRNA and protein content for L-FABP and H-FABP were analyzed. 16 h after administration, LPS (100 microg/100 g body weight) produced a 72% decrease in L-FABP mRNA levels in liver and this effect was sustained for 24 h. LPS also produced a 41% decrease in the protein content of L-FABP in liver after 24 h of treatment. TNF-alpha and IL-1beta decreased L-FABP mRNA levels in liver by 30 and 45%, respectively. LPS decreased H-FABP mRNA levels in skeletal muscle by 60% and in heart by 65%. LPS also produced a 49% decrease in H-FABP protein content in muscle. Neither TNF-alpha nor IL-1beta had any significant effect on H-FABP mRNA expression in heart and muscle. Taken together, these results indicate that LPS decreases FABP mRNA and protein levels in liver, heart and muscle, tissues that normally utilize FA as their primary fuel, whereas the inhibitory effect of cytokines is limited to the liver. The LPS-induced decrease in L-FABP and H-FABP may be an additional mechanism contributing to the decrease in FA oxidation that is associated with the host response to infection and inflammation.     

Peroxisomal proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha) enhances the thyroid hormone induction of carnitine palmitoyltransferase I (CPT-I alpha)

Carnitine palmitoyltransferase I (CPT-I) catalyzes the rate-controlling step in the pathway of mitochondrial fatty acid oxidation. Thyroid hormone will stimulate the expression of the liver isoform of CPT-I (CPT-I alpha). This induction of CPT-I alpha gene expression requires the thyroid hormone response element in the promoter and sequences within the first intron. The peroxisomal proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha) is a coactivator that promotes mitochondrial biogenesis, mitochondrial fatty acid oxidation, and hepatic gluconeogenesis. In addition, PGC-1 alpha will stimulate the expression of CPT-I alpha in primary rat hepatocytes. Here we report that thyroid hormone will increase PGC-1 alpha mRNA and protein levels in rat hepatocytes. In addition, overexpression of PGC-1 alpha will enhance the thyroid hormone induction of CPT-I alpha indicating that PGC-1 alpha is a coactivator for thyroid hormone. By using chromatin immunoprecipitation assays, we show that PGC-1 alpha is associated with both the thyroid hormone response element in the CPT-I alpha gene promoter and the first intron of the CPT-I alpha gene. Our data demonstrate that PGC-1 alpha participates in the stimulation of CPT-I alpha gene expression by thyroid hormone and suggest that PGC-1 alpha is a coactivator for thyroid hormone.