Hepatic regulation of platelet-activating factor acetylhydrolase and lecithin: Cholesterol acyltransferase biliary and plasma output in rats exposed to bacterial lipopolysaccharide

Abstract

Normal rat bile contains secretory platelet-activating factor acetylhydrolase (PAF-AH), the enzyme capable of hydrolyzing the inflammatory mediator platelet-activating factor (PAF), and phospholipids containing oxidized truncated fatty acids. Because lecithin:cholesterol acyltransferase (LCAT) possesses intrinsic PAF-AH-like activity, it also may represent a potential anti-inflammatory enzyme. The behavior of PAF-AH and LCAT in hepatobiliary inflammatory responses in vivo has not been characterized. We therefore investigated the biliary and plasma secretion and pharmacological characteristics of these enzymes in rats subjected to intraportal bacterial endotoxin exposure (lipopolysaccharide [LPS], Escherichia coli, 055:B5). Portal vein LPS infusion (1 mg/kg, bolus) resulted in a maximal 4-to 5-fold increase in bile PAF-AH-specific activity with a gradual decline to baseline by 18 hours. Biliary PAF-AH hydrolyzed also the truncated sn-2-succinoyl and sn-2-glutaroyl analogs of PAF, indicating a broader activity of PAF-AH in bile toward byproducts of glycerophospholipid peroxidation. Plasma PAF-AH activity was not altered 5 hours after LPS injection compared with saline injection, but it was significantly elevated 18 hours after endotoxin exposure. The levels of LCAT in bile were low and declined to nearly undetectable values by 5 hours after cannulation in both control and LPS-exposed rats. Plasma LCAT activity was significantly increased after 5 hours and decreased 18 hours after LPS injection. In summary, hepatic exposure to endotoxin results in a rapid increase in biliary secretion of PAF-AH followed by elevation of LCAT and PAF-AH levels in plasma. We propose that biliary secretion of PAF-AH may be involved in the hepatic response to endotoxic insult by counteracting potential inflammatory damage in the biliary tree and gastrointestinal tract, whereas plasma increases in LCAT and PAF-AH may promote elimination of excess PAF and oxidized phospholipids in the circulation. (HEPATOLOGY 1999;30:128-136.)

The elevation of apoB in hypercholesterolemic patients is primarily attributed to the relative increase of apoB/Lp-PLA2

“…Thus, the release of Lp-PLA 2 occurs independently of lipoprotein secretion; the enzyme subsequently associates with these particles ( 1 ). Lp-PLA 2 is actively produced and secreted by monocyte-derived macrophages in response to infl ammatory cytokines and microbial lipopolysaccharides (43)(44)(45)(46)(47). Hypercholesterolemic patients exhibit a low grade infl ammation, as is indicated by the higher hsCRP levels compared with controls, a fi nding that is in accordance with our previously published results ( 48 ).…”

Decrease of Plasma Platelet-Activating Factor Acetylhydrolase Activity in Lipopolysaccharide Induced Mongolian Gerbil Sepsis Model

“…[9] (Table 2). Although the reason for the different effects of LPS in C57BL/6 mice was yet to be elucidated, the present study, together with the studies in Syrian hamsters, rats, and C57BL/6 mice challenged by LPS [14], [15], [16], [17] (Table 2), showed that, among rodent species, only the gerbil demonstrated the decrease of pPAF-AH activity under the exposure of LPS (Figure 1), which was similar to the response of pPAF-AH measured in sepsis patients [7], [9], [10], [11]. Therefore, the LPS-induced sepsis in gerbil could be used to study the pharmacological effect of recombinant pPAF-AH in sepsis, and may provide pre-clinical evaluation of pPAF-AH in sepsis for the additional clinical trials in the future.…”

Lipoprotein‐associated phospholipase A2: The story continues

“…In male SD rats, Svetlov et al described a maximal four‐ to fivefold increase in bile Lp‐PLA2‐specific activity at approximately 2.5 hours after LPS infusion, followed by a gradual decline to baseline levels within 18 hours. However, plasma Lp‐PLA2 activity was significantly elevated 18 hours after LPS exposure, whereas no difference was detected at 5 hours compared with saline injection . In Syrian hamsters, the liver, spleen, lung, and small intestine exhibited strikingly increased Lp‐PLA2 mRNA levels after a 16 hours exposure to LPS, and the increase in plasma peaked at 24 hours and was sustained for at least 48 hours .…”

“…However, plasma Lp-PLA2 activity was significantly elevated 18 hours after LPS exposure, whereas no difference was detected at 5 hours compared with saline injection. 135 In Syrian hamsters, the liver, spleen, lung, and small intestine exhibited strikingly increased Lp-PLA2 mRNA levels after a 16 hours exposure to LPS, and the increase in plasma peaked at 24 hours and was sustained for at least 48 hours. 136 The increased plasma Lp-PLA2 activity was also determined in two other studies after LPS administration in C57BL/6 mice.…”