Deficiency of periostin protects mice against methionine-choline-deficient diet-induced non-alcoholic steatohepatitis
Authors: Yuan Li, Shasha Wu, Shanshan Xiong, Gaoliang Ouyang
Journal: Journal of Hepatology (2014)

Non-alcoholic fatty liver disease (NAFLD), the most common cause of chronic liver disease worldwide, encompasses a spectrum of diseases ranging from simple steatosis to non-alcoholic steatohepatitis (NASH) [1Bechmann L.P. Hannivoort R.A. Gerken G. Hotamisligil G.S. Trauner M. Canbay A. The interaction of hepatic lipid and glucose metabolism in liver diseases.J Hepatol. 2012; 56: 952-964Abstract Full Text Full Text PDF PubMed Scopus (596) Google Scholar, 2Michelotti G.A. Machado M.V. Diehl A.M. NAFLD, NASH and liver cancer.Nat Rev Gastroenterol Hepatol. 2013; 10: 656-665Crossref PubMed Scopus (677) Google Scholar]. Periostin (encoded by POSTN), a matricellular protein, plays an important role in various inflammatory disorders, such as airway inflammation, skin inflammation, atherosclerosis and fibrosis [3Conway S.J. Izuhara K. Kudo Y. Litvin J. Markwald R. Ouyang G. et al.The role of periostin in tissue remodeling across health and disease.Cell Mol Life Sci. 2014; 71: 1279-1288Crossref PubMed Scopus (263) Google Scholar, 4Liu A.Y. Zheng H. Ouyang G. Periostin, a multifunctional matricellular protein in inflammatory and tumor microenvironments.Matrix Biol. 2014; 37C: 150-156Crossref PubMed Scopus (129) Google Scholar], and actively contributes to tumour metastasis [5Bao S. Ouyang G. Bai X. Huang Z. Ma C. Liu M. et al.Periostin potently promotes metastatic growth of colon cancer by augmenting cell survival via the Akt/PKB pathway.Cancer Cell. 2004; 5: 329-339Abstract Full Text Full Text PDF PubMed Scopus (462) Google Scholar, 6Malanchi I. Santamaria-Martinez A. Susanto E. Peng H. Lehr H.A. Delaloye J.F. et al.Interactions between cancer stem cells and their niche govern metastatic colonization.Nature. 2012; 481: 85-89Crossref Scopus (970) Google Scholar, 7Wang Z. Ouyang G. Periostin: a bridge between cancer stem cells and their metastatic niche.Cell Stem Cell. 2012; 10: 111-112Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar]. However, until the recent publication by Lu et al. [[8]Lu Y. Liu X. Jiao Y. Xiong X. Wang E. Wang X. et al.Periostin promotes liver steatosis and hypertriglyceridemia through downregulation of PPARalpha.J Clin Invest. 2014; 124: 3501-3513Crossref PubMed Scopus (97) Google Scholar], there was no known link between periostin and NAFLD. Lu et al. [[8]Lu Y. Liu X. Jiao Y. Xiong X. Wang E. Wang X. et al.Periostin promotes liver steatosis and hypertriglyceridemia through downregulation of PPARalpha.J Clin Invest. 2014; 124: 3501-3513Crossref PubMed Scopus (97) Google Scholar] found that hepatic periostin expression is dramatically increased in high-fat diet (HFD)-fed mice, ob/ob mice and db/db mice, as well as in NAFLD patients. Lu et al. [[8]Lu Y. Liu X. Jiao Y. Xiong X. Wang E. Wang X. et al.Periostin promotes liver steatosis and hypertriglyceridemia through downregulation of PPARalpha.J Clin Invest. 2014; 124: 3501-3513Crossref PubMed Scopus (97) Google Scholar] further demonstrated that periostin is a crucial contributing factor in aberrant hepatic triglyceride (TG) accumulation and in the pathogenesis of obesity-induced hepatosteatosis. However, the role of periostin in the pathogenesis of NASH remains unknown [[9]Wu T. Wu S. Ouyang G. Periostin: a new extracellular regulator of obesity-induced hepatosteatosis.Cell Metab. 2014; 20: 562-564Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar]. As an aggressive form of fatty liver disease, NASH is characterized by histopathological features, such as steatosis, inflammation and fibrosis, and is often accompanied by the metabolic syndrome, such as diabetes, insulin resistance and obesity. Moreover, some individuals with NASH eventually advance to liver cirrhosis and/or hepatocellular carcinoma, whereas hepatic steatosis usually has no serious clinical consequences [2Michelotti G.A. Machado M.V. Diehl A.M. NAFLD, NASH and liver cancer.Nat Rev Gastroenterol Hepatol. 2013; 10: 656-665Crossref PubMed Scopus (677) Google Scholar, 9Wu T. Wu S. Ouyang G. Periostin: a new extracellular regulator of obesity-induced hepatosteatosis.Cell Metab. 2014; 20: 562-564Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar]. Because genetically induced rodent obesity or HFD-induced hepatic steatosis does not progress to steatohepatitis, we now present data to determine the role of periostin in the development of methionine-choline-deficient (MCD) diet-induced NASH in mice. To reveal the role of periostin in the development of NASH, we fed two groups of C57BL/6J mice with either regular chow or the MCD diet for 4 weeks. MCD diet-fed mice developed hepatic steatosis whereas chow-fed mice did not develop steatosis. The MCD diet also resulted in inflammation and fibrosis in mouse liver tissue (data not shown). We found that periostin was markedly upregulated and mainly distributed around steatotic hepatocytes in the MCD diet-fed mice by immunohistochemical staining (Fig. 1A). Western blotting and qRT-PCR analyses further demonstrated that the protein and mRNA levels of liver periostin were dramatically increased in MCD diet-fed mice compared with control mice (Fig. 1B and C). Moreover, we found that mice fed the MCD diet for 8 weeks, also developed NASH and showed phenotypes of steatosis, inflammation and fibrosis. The protein and mRNA levels of liver periostin in mice fed the MCD diet for 8 weeks were also significantly upregulated (data not shown). These data suggest that periostin may be involved in the development of MCD diet-induced NASH. To determine whether periostin deficiency abrogates the progression of NASH, we used a periostin-deficient mouse model. Heterozygous B6;129-Postntm1Jmol/J (Postn+/−) mice were purchased from the Jackson Laboratory (Bar Harbor, Maine, USA). Periostin-deficient and periostin wild type mice were generated from crossing Postn+/− with Postn+/− mice. After feeding the MCD diet for 4 weeks, periostin-deficient mice exhibited significantly less TGs in their livers compared to the wild type group (Fig. 1D). The serum level of alanine aminotransferase was markedly decreased in Postn−/− mice compared to wild type mice (Fig. 1E), indicating that the MCD diet produced a more severe liver injury in wild type mice than in Postn−/− mice. Moreover, MCD diet feeding resulted in an increased collagen deposition in wild type mice, as shown by Sirius red staining; however, collagen deposition was significantly lower in Postn−/− mice than in wild type mice after being on the MCD diet (Fig. 1F and G), suggesting that Postn−/− mice exhibited significantly less histological fibrosis compared to the wild type group. We also found that mRNA levels of the inflammatory and fibrotic factors IL-6, TGF-β1, and α-SMA were markedly increased in livers of MCD diet-fed wild type mice compared to the chow diet-fed wild type controls; however, the mRNA levels of IL-6, TGF-β1, and α-SMA were significantly lower in the liver tissue of Postn−/− mice than in wild type mice after being on the MCD diet for 4 weeks (Fig. 1H). Therefore, these data suggest that a deficiency in periostin abrogates the development of MCD diet-induced NASH in mice. In conclusion, our work demonstrates that periostin is highly expressed in MCD diet-induced NASH and that periostin knockout mice show a markedly lower degree of steatosis, inflammation and fibrosis compared with wild type mice after being fed the MCD diet. As previously mentioned, hepatic periostin levels are significantly upregulated in monogenic-induced obese mice and HFD-fed mice, as well as in patients with fatty liver disease [[8]Lu Y. Liu X. Jiao Y. Xiong X. Wang E. Wang X. et al.Periostin promotes liver steatosis and hypertriglyceridemia through downregulation of PPARalpha.J Clin Invest. 2014; 124: 3501-3513Crossref PubMed Scopus (97) Google Scholar]. Therefore, these data demonstrate that periostin is a potential diagnostic marker and therapeutic target for hepatosteatosis, NASH and even other liver diseases. This work was supported by grants from the National Nature Science Foundation of China (81372841, 31171339, 31071302), the Program for New Century Excellent Talents in University (NCET-11-0296) and the Scientific Fund for Distinguished Young Investigator of Fujian Province (2010J06013). The authors who have taken part in this study declare that they do not have anything to disclose regarding conflict of interest with respect to this manuscript.