Lipid Synthesis in Macrophages during Inflammation in vivo: Effect of Agonists of Peroxisome Proliferator Activated Receptors alpha and gamma and of Retinoid X Receptors

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E. N. Posokhova¹, O. M. Khoshchenko¹, M. I. Chasovskikh², E. N. Pivovarova³, and M. I. Dushkin^2*

¹Institute of Internal Medicine, Siberian Branch of the Russian Academy of Medical Sciences, ul. B. Bogatkova 175/1, 630089 Novosibirsk, Russia; fax: (383) 264-2516

²Institute of Clinical Immunology, Siberian Branch of the Russian Academy of Medical Sciences, ul. Yadrintsevskaya 14, 630099 Novosibirsk, Russia; fax: (383) 334-8373; E-mail: midushkin@soramn.ru

³Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, pr. Lavrent'eva 10, 630090 Novosibirsk, Russia; fax: (383) 333-1278

^* To whom correspondence should be addressed.

Received April 27, 2007; Revision received September 14, 2007

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The effects of peroxisome proliferator activated receptors alpha and gamma (PPAR-alpha and PPAR-gamma) and retinoid X receptor (RXR) agonists upon synthesis and accumulation of lipids in murine C57Bl macrophages during inflammation induced by injection of zymosan and Escherichia coli lipopolysaccharide (LPS) have been studied. It is significant that intraperitoneal injection of zymosan (50 mg/kg) or LPS (0.1 mg/kg) in mice led to a dramatic increase of [¹⁴C]oleate incorporation into cholesteryl esters and triglycerides and [¹⁴C]acetate incorporation into cholesterol and fatty acids in peritoneal macrophages. Lipid synthesis reached its maximum rate 18-24 h after injection and was decreased 5-7 days later to control level after LPS injection or was still heightened after zymosan injection. In macrophages obtained in acute phase of inflammation (24 h), degradation of ¹²⁵I-labeled native low density lipoprotein (NLDL) was 4-fold increased and degradation of ¹²⁵I-labeled acetylated LDL (AcLDL) was 2-3-fold decreased. Addition of NLDL (50 µg/ml) or AcLDL (25 µg/ml) into the incubation medium of activated macrophages induced 9-14- and 1.25-fold increase of cholesteryl ester synthesis, respectively, compared with control. Addition of NLDL and AcLDL into the incubation medium completely inhibited cholesterol synthesis in control macrophages but had only slightly effect on cholesterol synthesis in activated macrophages. Injection of RXR, PPAR-alpha, or PPAR-gamma agonists--9-cis-retinoic acid (5 mg/kg), bezafibrate (10 mg/kg), or rosiglitazone (10 mg/kg), respectively--30 min before zymosan or LPS injection led to significant decrease of lipid synthesis. Ten hour preincubation of activated in vivo macrophages with the abovementioned agonists (5 µM) decreased cholesteryl ester synthesis induced by NLDL and AcLDL addition into the cell cultivation medium. The data suggest that RXR, PPAR-alpha, or PPAR-gamma agonists inhibited lipid synthesis and induction of cholesteryl ester synthesis in inflammatory macrophages caused by capture of native or modified LDL.

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KEY WORDS: macrophages, lipid metabolism, PPAR, RXR, inflammation

DOI: 10.1134/S0006297908030097

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