title: Curcumin Protects Against Intestinal Origin Endotoxemia in Rat Liver Cirrhosis by Targeting PCSK9.
abstract: Intestinal origin endotoxemia always occurs in severe liver injury. The aim of the current study was to test antiendotoxemia effect of curcumin on tetrachloride (CCl4)-induced liver cirrhosis rats, and to elucidate the underlying molecular mechanism. Rat cirrhosis models were constructed with CCl4subcutaneous injections with curcumin (200 mg/kg/d) administered via gavages for 12 wk until the rats were sacrificed. We found that the administration of curcumin improved the physiological condition pertaining to activity index and temperature, and ameliorated the liver injury in CCl4-induced cirrhosis rats. Enzyme-linked immunosorbent assay (ELISA) and real-time quantitative polymerase chain reaction (qRT-PCR) showed that curcumin could reduce c-reaction protein levels and inflammatory cytokine (TNF-α, IL-1β, IL-6, and CINC-1/IL-8) concentrations in peripheral serum and liver tissue. Furthermore, curcumin treatment decreased lipopolysaccharide (LPS) levels in peripheral vein, but not in portal vein. As low-density lipoprotein receptor (LDLR) is the important receptor on the surface of hepatocyte during LPS detoxification process, we used qRT-PCR, western blot, and immunohistochemistry (IHC), finding that curcumin significantly increased LDLR protein levels, but not gene levels in the liver tissues. We also tested proprotein convertase subtilisin/kexin type 9 (PCSK9), one negative regulator of LDLR, by qRT-PCR, western blot, and IHC. The results showed that PCSK9 significantly decreased both gene and protein levels in the rat liver tissues of curcumin treatment. Thus, we concluded that curcumin could function to protect against intestinal origin endotoxemia by inhibiting PCSK9 to promote LDLR expression, thereby enhancing LPS detoxification as one pathogen lipid through LDLR in the liver.
authors.affiliation: Dept. of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan Univ., 180 Fenglin Rd., Xuhui District, Shanghai, P.R. China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Dept. of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan Univ., 180 Fenglin Rd., Xuhui District, Shanghai, P.R. China.
authors.forename: Di
authors.initials: D
authors.lastname: Lu
authors.affiliation: Dept. of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan Univ., 180 Fenglin Rd., Xuhui District, Shanghai, P.R. China.
authors.forename: Yanting
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Dept. of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan Univ., 180 Fenglin Rd., Xuhui District, Shanghai, P.R. China.
authors.forename: Chaohui
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Dept. of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan Univ., 180 Fenglin Rd., Xuhui District, Shanghai, P.R. China.
authors.forename: Hongchun
authors.initials: H
authors.lastname: Liu
authors.affiliation: Dept. of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan Univ., 180 Fenglin Rd., Xuhui District, Shanghai, P.R. China.
authors.forename: Chuantao
authors.initials: C
authors.lastname: Tu
authors.affiliation: Dept. of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan Univ., 180 Fenglin Rd., Xuhui District, Shanghai, P.R. China.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.affiliation: Dept. of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan Univ., 180 Fenglin Rd., Xuhui District, Shanghai, P.R. China.
authors.forename: Lili
authors.initials: L
authors.lastname: Liu
authors.affiliation: Dept. of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan Univ., 180 Fenglin Rd., Xuhui District, Shanghai, P.R. China.
authors.forename: Shuncai
authors.initials: S
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D002251:Carbon Tetrachloride; D056486:Chemical and Drug Induced Liver Injury / Q000150:complications / Q000473:pathology; D054360:Chemokine CXCL1 / Q000097:blood; D030024:Curcuma / Q000737:chemistry; D003474:Curcumin / Q000494:pharmacology* / Q000627:therapeutic use; D016207:Cytokines / Q000097:blood; D019446:Endotoxemia / Q000209:etiology / Q000517:prevention & control; D006801:Humans; D007422:Intestines / Q000187:drug effects* / Q000473:pathology; D008070:Lipopolysaccharides / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology* / Q000627:therapeutic use; D000071449:Proprotein Convertase 9 / Q000378:metabolism*; D051381:Rats; D011973:Receptors, LDL / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D054360:Chemokine CXCL1; C513297:Cxcl1 protein, rat; D016207:Cytokines; D008070:Lipopolysaccharides; D008077:Lipoproteins, LDL; D010936:Plant Extracts; D011973:Receptors, LDL; D002251:Carbon Tetrachloride; D000071449:Proprotein Convertase 9; D003474:Curcumin
keywords: curcumin; intestinal origin endotoxemia; liver cirrhosis; low-density lipoprotein receptor (LDLR); proprotein convertase subtilisin/kexin type 9 (PCSK9)