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1 Department of Medicine, University of California, San Francisco 94143; Metabolism Section, Medical Service, Department of Veterans Affairs Medical Center, San Francisco, California 94121; and 2 Ross Products Division, Abbott Laboratories, Columbus, Ohio 43215
Acyl-CoA synthetase (ACS) catalyzes the activation of fatty
acids (FA) to acyl-CoA esters, which are further metabolized in either
anabolic or catabolic pathways. Endotoxin [lipopolysaccharide (LPS)], tumor necrosis factor (TNF), and interleukin-1 (IL-1) enhance hepatic FA synthesis and reesterification and inhibit FA
oxidation. LPS also decreases triglyceride storage in adipose tissue
and inhibits the uptake of FA by heart and muscle. Therefore, in this
study we examined the effects of LPS and cytokines on ACS (now also
known as ACS1) mRNA expression and activity in multiple tissues in
Syrian hamsters. LPS markedly decreased ACS1 mRNA levels in liver,
adipose tissue, heart, and skeletal muscle. The inhibitory effects of
LPS on ACS1 mRNA levels in liver and adipose tissue were observed as
early as 2-4 h after administration, became maximal by 4-8 h,
and were sustained for 
24 h. Very low doses of LPS (0.1-1
µg/100 g body wt) were needed to reduce ACS1 mRNA levels in liver and
adipose tissue. TNF and IL-1 mimicked the effect of LPS on ACS1 mRNA
levels in liver and adipose tissue. LPS decreased ACS activity in
adipose tissue, heart, and muscle. In liver, where ACS is localized in
several subcellular organelles, both LPS and cytokines decreased
mitochondrial ACS activity, whereas they increased microsomal ACS
activity. Taken together, these results indicate that LPS and cytokines
decrease ACS1 mRNA expression and ACS activity in tissues where FA
uptake and/or oxidation is decreased during sepsis. In liver,
where FA oxidation is decreased during sepsis but the reesterification
of FA is increased, LPS and cytokines decrease ACS1 mRNA and
mitochondrial ACS activity, which may inhibit FA oxidation, but
increase microsomal ACS activity, which may support the
reesterification of peripherally derived FA for triglyceride synthesis.
tumor necrosis factor; interleukin-1; sepsis; fatty acid oxidation; fatty acid transport
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