No abstract

Background and Purpose Intrahepatic cholestasis is mainly caused by dysfunction of bile secretion and has limited effective treatment. Rosiglitazone is a synthetic agonist of PPARγ, whose endogenous agonist is 15‐deoxy‐Δ12,14‐PGJ2 (15d‐PGJ2). Reticulon 4B (Nogo‐B) is the detectable Nogo protein family member in the liver and secreted into circulation. Here, we determined if rosiglitazone can alleviate intrahepatic cholestasis in mice. Experimental Approach Wild‐type, hepatocyte‐specific PPARγ or Nogo‐B knockout mice received intragastric administration of α‐naphthylisothiocyanate (ANIT) and/or rosiglitazone, followed by determination of intrahepatic cholestasis and the involved mechanisms. Serum samples from primary biliary cholangitis (PBC) patients and non‐PBC controls were analysed for cholestasis‐related parameters. Key Results Rosiglitazone prevented wild type, but not hepatocyte‐specific PPARγ deficient mice from developing ANIT‐induced intrahepatic cholestasis by increasing expression of bile homeostatic proteins, reducing hepatic necrosis, and correcting abnormal serum parameters and enterohepatic circulation of bile. Nogo‐B knockout provided protection similar to that of rosiglitazone treatment. ANIT‐induced intrahepatic cholestasis decreased 15d‐PGJ2 but increased Nogo‐B in serum, and both were corrected by rosiglitazone. Nogo‐B deficiency in the liver increased 15d‐PGJ2 production, thereby activating expression of PPARγ and bile homeostatic proteins. Rosiglitazone and Nogo‐B deficiency also alleviated cholestasis‐associated dyslipidemia. In addition, rosiglitazone reduced symptoms of established intrahepatic cholestasis in mice. In serum from PBC patients, the decreased 15d‐PGJ2 and increased Nogo‐B levels were significantly correlated with classical cholestatic markers. Conclusions and Implications Levels of 15d‐PGJ2 and Nogo are important biomarkers for intrahepatic cholestasis. Synthetic agonists of PPARγ could be used for treatment of intrahepatic cholestasis and cholestasis‐associated dyslipidemia.

Background: Alcohol-related liver disease (ALD) is a major cause of chronic liver diseases, and the inflammatory response is a basic pathological feature of ALD. Immunity throughout different stages of ALD has not yet been elucidated. The mucosal-associated invariant T(MAIT) cells are a novel population of innate immune cells, which may be depleted in various inflammatory diseases. However, the mechanism of MAIT cell loss in ALD remains unclear.Results: In this study, we found that MAIT cells were depleted in patients with alcoholic fatty liver disease, alcoholic cirrhosis, and mixed cirrhosis (alcoholic + viral). Furthermore, the reduction in circulating MAIT cells was correlated with liver function in patients with cirrhosis. We detected functional changes among circulating MAIT cells in patients with alcoholic cirrhosis, including increased production of IL-17A and perforin, and reduced production of TNF-α. Plasma cytokine and chemokine levels were quantified using multiple immunoassays and ELISA. Serum levels of chemokine IL-8 were correlated with MAIT cell frequency in patients with alcoholic cirrhosis. Moreover, no differences were observed in the expression of CCR6, CXCR6, and PD-1 in circulating MAIT cells of patients with alcoholic cirrhosis. The MAIT cells in patients with alcoholic cirrhosis were prone to apoptosis, which was promoted by IL-12, IL-18, and IL-8. Conclusions: Our findings indicate persistent MAIT cell loss during alcohol-related liver disease, and suggest that MAIT cells can be promising indicator and therapeutic targets in ALD.

Background Alcohol-related liver disease (ALD) is a major cause of chronic liver diseases. Inflammatory response is a basic pathological feature of ALD. Mucosal-associated invariant T(MAIT) cells are a novel population of innate immune cells, which may be depleted in various inflammatory diseases. However, the changes of MAIT cell in ALD remains unclear. Results In this study, the levels of MAIT cell were significantly decreased in patients with alcoholic fatty liver disease, alcoholic cirrhosis, and mixed cirrhosis (alcoholic + viral). Furthermore, the reduction of circulating MAIT cells was correlated with liver function in patients with cirrhosis. Functional changes among circulating MAIT cells in patients with alcoholic cirrhosis, including increased production of IL-17A and perforin, and reduced production of TNF-α. Plasma cytokine and chemokine levels were quantified using multiple immunoassays and ELISA. Serum levels of chemokine IL-8 were correlated with MAIT cell frequency in patients with alcoholic cirrhosis. Moreover, no differences were observed in the expression of CCR6, CXCR6, and PD-1 in circulating MAIT cells of patients with alcoholic cirrhosis. The MAIT cells in patients with alcoholic cirrhosis were prone to apoptosis, which was promoted by IL-12, IL-18, and IL-8. Conclusions Our findings indicate persistent MAIT cell loss during alcohol-related liver disease and suggest that MAIT cells can be promising indicator and therapeutic targets in ALD.