Curcumin ameliorates hepatic chronic inflammation induced by bile duct obstruction in mice through the activation of heme oxygenase-1

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Highlights

Introduction

Many hepatic diseases, such as gallstones, obstructive jaundice, acute hepatitis, biliary atresia, cystic fibrosis, primary sclerosing cholangitis and primary biliary cirrhosis, often lead to hepatic cholestasis [1]. The blockage of bile flow from the hepatocytes to the intestine leads to bile acid accumulation in the liver tissue, resulting in inflammation, oxidative stress, apoptosis and fibrosis. Nevertheless, ursodeoxycholic acid and obeticholic acid is the only clinically approved treatment for chronic cholestatic liver disease until now [2]. Nowadays, there are no anti-inflammatory agent available to inhibit inflammation induced by chronic hepatic cholestasis. Therefore, it is extremely important to develop new anti-inflammatory components for cholestasis.

It has been recognized that bioactive foods and natural products have antifibrotic effects. Identification of natural products and bioactive food components is vital to develop effective preventive/therapeutic strategies against hepatic fibrosis [3]. Curcumin (Cur), a natural yellow polyphenol, is isolated from rhizome of turmeric (Curcuma longa). Cur has anti-oxidant, anti-inflammatory, anti-mutagenic and anti-carcinogenic properties and is expected to treat and to have prophylactic effects on different diseases [4], [5]. Additionally, more and more studies have unequivocally recognized that Cur has powerful hepatoprotective effects. Cur significantly attenuated TNF-α-induced liver steatosis [6] and CCl4- induced acute liver injury in rats [7]; Cur also could recover the lipid metabolism homeostasis in oleic acid-stimulated hepatocarcinoma cells [8]. However, the molecular mechanisms underlying the protective role of Cur on hepatic diseases has not been fully explored.

Heme oxygenase-1 (HO-1) exerts antioxidant anti-inflammatory and cytoprotective effects through its by-products by degrading heme [9], [10]. Several studies have reported that Cur could up-regulated HO-1 and dampened various liver diseases such as acute liver injury, alcoholic liver disease and liver fibrosis [11], [12], [13], but it is not clear that the role of HO-1 on the protective effect of Cur against hepatic cholestasis. In this study, we found that HO-1 contributed to the protective effect of Cur against hepatic cholestasis in BDL mice.

Section snippets

Reagents and antibodies

Curcumin (Cat # C1386, purity ≥ 95% by HPLC), zinc protoporphyrin IX (ZnPP, Cat # 282820, purity ≥ 95% by HPLC), P450 reductase (Cat #C8113), β-NADPH (Cat #N5130) were purchased from Sigma-Aldrich Chemical (St. Louis, MO, USA). Aspartate aminotransferase (AST), alanine aminotransferase (ALT) were purchased from Nanjing Jiancheng (China). Primary antibodies for anti-HO-1 (Cat # ab13248), MPO (Cat # ab9535) were obtained from Abcam (Abcam, USA). F4/80 (Cat #MCA497GA) and 4′,6-

The abnormal liver function and serious liver fibrosis in BDL mice

We performed operation of bile duct ligation in 20 male mice and euthanized them at 7 d and 14 d after surgery to investigate different phase of liver fibrogenesis. Compared with the control group and sham group mice, the gall bladders of BDL mice were filled with large quantities of bile at the 7th day and even aggravated after 14 days (Fig. 1A). At the 7th day, the content of ALT and AST was higher than 14th day while the total bilirubin and direct bilirubin constantly increased during the

Discussion

Although Cur has received more attention over the years as a promising preventive and treatment agent for many hepatic diseases, its defined mechanisms on hepatoprotective effects are largely unknown. In this study, we demonstrated for the first time that Cur could up-regulated the expression and activities of HO-1, and facilitated its nuclear translocation. Noteworthily, Cur could effectively reverse this abnormal lipid metabolism in BDL mice. HO-1 activity inhibitor (ZnPP), abolished these

Declaration of Competing Interest

The authors declared that there is no conflict of interest.

Acknowledgments

This study was supported by the grants from the project supported by the following grants: National Natural Science Foundation of China, China (81871518, 81901522, 81702799); National first-class discipline program of Food Science and Technology, China (JUFSTR20180101); Wuxi health and family planning commission, China (Z201810); Public Health Research center at Jiangnan University, China (JUPH201805); Fundamental Research Funds for the Central Universities, China (JUSRP11955).

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These authors contributed equally to this work.

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