Peroxisomes are now recognized to play important role in cellular metabolism of saturated and unsaturated fatty acids, arachidonic acid metabolites, cholesterol and plasmalogens and more than 16 inherited disorders have been identified with defects in one or more than one of these peroxisomal functions. We previously observed that a sublethal dose of LPS decreases the amount of peroxisomes as well as alters their lipid composition, suggesting that these peroxisomal alterations must be critical factors in LPS-induced injury. To understand the mechanism of LPS-induced alterations in peroxisomes, we investigated the effect of kupffer cell inactivation/elimination by gadolinium chloride(i.v., 10 mg/kg body weight) on LPS-induced(i.p., 1 mg/kg body weight) lipid alterations and fatty acid compositions of rat liver peroxisomes. Gadolinium chloride treatment of rats results in inactivation/elimination of kupffer cells. LPS-induced decrease(30-40%,p<0.01 vs. control) in the ratio of phospholipids/cholesterol was reversed back to normal levels following inactivation/elimination of kupffer cell. LPS-induced altered unsaturation index (p<0.05 vs. control), n-3/n-6 fatty acid ratio (p<0.05 vs. control) and concentration of VLCFA were also normalized in animals treated with gadolinium chloride plus LPS. However, instead of normalization of plasmalogens content of peroxisomes, the pretreatment with gadolinium chloride further increased the content of plasmalogen (80-100%, p<0.01) in peroxisomes of LPS- treated rat liver. This study demonstrates an involvement of kupffer cell metabolites/mediators in LPS-induced alterations in lipids and fatty acid compositions in rat liver peroxisomes, suggesting a role of these in modulating the peroxisomal functions in endotoxemia.

Supported by grants NS-22576 from N.I.H.