Tim Hendrikx1, Mike L J Jeurissen1, Veerle Bieghs1, Sofie M A Walenbergh1, Patrick J van Gorp1, Fons Verheyen1, Tom Houben1, Yasmin Dias Guichot1, Marion J J Gijbels1, Eran Leitersdorf2, Marten H Hofker3, Dieter Lütjohann4, Ronit Shiri-Sverdlov5. 1. Department of Molecular Genetics, ELMI Unit (CRISP) and Pathology, Nutrition and Toxicology Research (NUTRIM) and Cardiovascular Research (CARIM), Institutes of Maastricht, University of Maastricht, Maastricht, The Netherlands; Department of Molecular Cell Biology, ELMI Unit (CRISP) and Pathology, Nutrition and Toxicology Research (NUTRIM) and Cardiovascular Research (CARIM), Institutes of Maastricht, University of Maastricht, Maastricht, The Netherlands. 2. Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. 3. Department of Pathology & Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. 4. Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany. 5. Department of Molecular Genetics, ELMI Unit (CRISP) and Pathology, Nutrition and Toxicology Research (NUTRIM) and Cardiovascular Research (CARIM), Institutes of Maastricht, University of Maastricht, Maastricht, The Netherlands; Department of Molecular Cell Biology, ELMI Unit (CRISP) and Pathology, Nutrition and Toxicology Research (NUTRIM) and Cardiovascular Research (CARIM), Institutes of Maastricht, University of Maastricht, Maastricht, The Netherlands. Electronic address: r.sverdlov@maastrichtuniversity.nl.
Abstract
BACKGROUND & AIMS: Non-alcoholic steatohepatitis (NASH) is characterized by hepatic lipid accumulation and inflammation. Currently, the underlying mechanisms, leading to hepatic inflammation, are still unknown. The breakdown of free cholesterol inside Kupffer cells (KCs) by the mitochondrial enzyme CYP27A1 produces 27-hydroxycholesterol (27HC). We recently demonstrated that administration of 27HC to hyperlipidemic mice reduced hepatic inflammation. In line, hematopoietic deletion of Cyp27a1 resulted in increased hepatic inflammation. In the current manuscript, the effect of hematopoietic overexpression of Cyp27a1 on the development of NASH and cholesterol trafficking was investigated. We hypothesized that Cyp27a1 overexpression in KCs will lead to reduced hepatic inflammation. METHODS: Irradiated Ldlr(-/-) mice were transplanted (tp) with bone marrow from mice overexpressing Cyp27a1 (Cyp27a1(over)) and wild type (Wt) mice and fed either chow or a high-fat, high-cholesterol (HFC) diet for 3 months. Additionally, gene expression was assessed in bone marrow-derived macrophages (BMDM) from Cyp27a1(over) and Wt mice. RESULTS: In line with our hypothesis, hepatic inflammation in HFC-fed Cyp27a1(over)-tp mice was reduced and KCs were less foamy compared to Wt-tp mice. Remarkably, these changes occurred even though plasma and liver levels of 27HC did not differ between both groups. BMDM from Cyp27a1(over) mice revealed reduced inflammatory gene expression and increased expression of cholesterol transporters compared to Wt BMDM after lipopolysaccharide (LPS) stimulation. CONCLUSIONS: Our data suggest that overexpression of Cyp27a1 in KCs reduces hepatic inflammation independently of 27HC levels in plasma and liver, further pointing towards KCs as specific target for improving the therapy of NASH.
BACKGROUND & AIMS:Non-alcoholic steatohepatitis (NASH) is characterized by hepatic lipid accumulation and inflammation. Currently, the underlying mechanisms, leading to hepatic inflammation, are still unknown. The breakdown of free cholesterol inside Kupffer cells (KCs) by the mitochondrial enzyme CYP27A1 produces 27-hydroxycholesterol (27HC). We recently demonstrated that administration of 27HC to hyperlipidemic mice reduced hepatic inflammation. In line, hematopoietic deletion of Cyp27a1 resulted in increased hepatic inflammation. In the current manuscript, the effect of hematopoietic overexpression of Cyp27a1 on the development of NASH and cholesterol trafficking was investigated. We hypothesized that Cyp27a1 overexpression in KCs will lead to reduced hepatic inflammation. METHODS: Irradiated Ldlr(-/-) mice were transplanted (tp) with bone marrow from mice overexpressing Cyp27a1 (Cyp27a1(over)) and wild type (Wt) mice and fed either chow or a high-fat, high-cholesterol (HFC) diet for 3 months. Additionally, gene expression was assessed in bone marrow-derived macrophages (BMDM) from Cyp27a1(over) and Wt mice. RESULTS: In line with our hypothesis, hepatic inflammation in HFC-fed Cyp27a1(over)-tpmice was reduced and KCs were less foamy compared to Wt-tp mice. Remarkably, these changes occurred even though plasma and liver levels of 27HC did not differ between both groups. BMDM from Cyp27a1(over)mice revealed reduced inflammatory gene expression and increased expression of cholesterol transporters compared to Wt BMDM after lipopolysaccharide (LPS) stimulation. CONCLUSIONS: Our data suggest that overexpression of Cyp27a1 in KCs reduces hepatic inflammation independently of 27HC levels in plasma and liver, further pointing towards KCs as specific target for improving the therapy of NASH.
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