Bone marrow-derived macrophage contributes to fibrosing steatohepatitis through activating hepatic stellate cells.

The role of macrophages in fibrosing steatohepatitis is largely unclear. We characterized the origin and molecular mechanisms of macrophages and its targeted therapy of fibrosing steatohepatitis. Fibrosing steatohepatitis was established in Alms1 mutant (foz/foz) and C57BL/6J wildtype mice fed high-fat/high-cholesterol or methionine- and choline-deficient diet. Bone marrow transplantation was performed to track the macrophage origin in fibrosing steatohepatitis. Macrophages were depleted using liposomal clodronate. Primary macrophages were isolated from bone marrow for adoptive transfer into mice. We found that macrophage infiltration is induced in two mouse models of fibrosing steatohepatitis and human nonalcoholic steatohepatitis-fibrosis patients. Bone marrow-derived macrophages (BMMs) contribute to the hepatic macrophage accumulation in experimental fibrosing steatohepatitis. Depletion of hepatic BMMs by liposomal clodronate during liver injury attenuated fibrosing steatohepatitis, whilst BMMs depletion after liver injury delayed the regression of fibrosing steatohepatitis. The pro-fibrotic effect of macrophages was associated with reduced activation of hepatic stellate cells (HSCs), collagen deposition and hepatic expression of key pro-fibrotic factors (TIMP1, TIMP2, and TGFß1) and endoplasmic reticulum stress markers (GRP78, IRE1α, and PDI). Conversely, adoptive transfer of BMMs significantly aggravated fibrosing steatohepatitis. Moreover, macrophage-conditioned medium directly promoted the phenotypic transition of primary quiescent HSCs to activated HSCs; it enhanced activation and proliferation but decreased apoptosis of HSC cell lines (LX-2 and HSC-T6). The effect of BMMs in promoting fibrosing steatohepatitis was mediated by inducing key pro-fibrosis factors and signaling pathways including cytokine/chemokine, TGFß and complement cascade as assessed by cDNA expression array. Complement 3a receptor (C3ar1) was a predominant effector of macrophage mediated fibrosing steatohepatitis. Knockout of C3ar1 in mice blunted development of fibrosing steatohepatitis. In conclusion, BMMs promoted the progression of fibrosing steatohepatitis during injury, whereas macrophages reduced fibrosing steatohepatitis in the recovery phase of liver injury. Increasing anti-fibrotic macrophages and decreasing pro-fibrotic macrophages are promising approaches for fibrosing steatohepatitis. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Bile acids, gut microbiota, and therapeutic insights in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a prevalent and aggressive liver malignancy. The interplay between bile acids (BAs) and the gut microbiota has emerged as a critical factor in HCC development and progression. Under normal conditions, BA metabolism is tightly regulated through a bidirectional interplay between gut microorganisms and BAs. The gut microbiota plays a critical role in BA metabolism, and BAs are endogenous signaling molecules that help maintain liver and intestinal homeostasis. Of note, dysbiotic changes in the gut microbiota during pathogenesis and cancer development can disrupt BA homeostasis, thereby leading to liver inflammation and fibrosis, and ultimately contributing to HCC development. Therefore, understanding the intricate interplay between BAs and the gut microbiota is crucial for elucidating the mechanisms underlying hepatocarcinogenesis. In this review, we comprehensively explore the roles and functions of BA metabolism, with a focus on the interactions between BAs and gut microorganisms in HCC. Additionally, therapeutic strategies targeting BA metabolism and the gut microbiota are discussed, including the use of BA agonists/antagonists, probiotic/prebiotic and dietary interventions, fecal microbiota transplantation, and engineered bacteria. In summary, understanding the complex BA-microbiota crosstalk can provide valuable insights into HCC development and facilitate the development of innovative therapeutic approaches for liver malignancy.