Toxic lipids stored by Kupffer cells correlates with their pro-inflammatory phenotype at an early stage of steatohepatitis

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• 作者：Anne Leroux¹ ; ² ; Gladys Ferrere¹ ; ² ; Vanessa Godie¹ ; ² ; Fr&eacute ; d&eacute ; ric Cailleux¹ ; ² ; Marie-Laure Renoud¹ ; ² ; Fran&ccedil ; oise Gaudin¹ ; ² ; ³ ; Sylvie Naveau¹ ; ² ; ⁴ ; Sophie Pr&eacute ; vot² ; ⁵ ; Samira Makhzami⁶ ; Gabriel Perlemuter¹ ; ² ; ⁴ ; Anne-Marie Cassard-Doulcier¹ ; ² ; ^{cassard.doulcier@u-psud.fr}
• 关键词：NASH ; non-alcoholic steatohepatitis ; LPS ; lipopolysaccharide ; KC ; Kupffer cell ; NAFLD ; non-alcoholic fatty liver disease ; TNF伪 ; tumor necrosis factor-伪 ; IFN纬 ; interferon-纬 ; IL ; interkeukin ; ND ; normal diet ; HFD ; high fat diet ; TG ; triacylglycerol ; NPC
• 刊名：Journal of Hepatology
• 出版年：2012
• 期刊代码：162_01688278
• 类别：med
• 出版时间：July, 2012
• 卷：57
• 期：1
• 页码：141-149
• 文件大小：1464 K

摘要

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Background & Aims

Non-alcoholic steatohepatitis (NASH) is characterized by steatosis associated with liver inflammation. Steatosis causes recruitment of lymphocytes into the liver and this is worsened by lipopolysaccharides (LPS). As macrophages may be involved in the lymphocyte homing, we studied the role of lipids in determining the phenotype of Kupffer cells (KCs) at the stage of steatosis.

Methods

Steatosis was induced in mice by a high fat diet. The turnover and the recruitment of KCs were analyzed in vivo by flow cytometry. KCs phenotype was assessed by optical and electron microscopy, cell culture and lymphocyte recruitment by in vitro chemotaxis. Lipidomic analysis was carried out by mass-spectrometry and gene expression analysis by TaqMan low density array.

Results

Although the number of KCs was not modified in steatotic livers compared to normal livers, their phenotypes were different. Electron microscopy demonstrated that the KCs from fatty livers were enlarged and loaded with lipid droplets. Lipid synthesis and trafficking were dysregulated in fat-laden KCs and toxic lipids accumulated. Fat-laden KCs recruited more CD4+ T and B lymphocytes in response to LPS stimulation than did control KCs and produced high levels of pro-inflammatory cytokines/chemokines, which could be reversed by inhibition of lipogenesis.

Conclusions

Lipid accumulation in fat-laden KCs is due to a dysregulation of lipid metabolism and trafficking. Fat-laden KCs are 鈥減rimed鈥?to recruit lymphocytes and exhibit a pro-inflammatory phenotype, which is reversible with inhibition of lipogenesis.