Vascular adhesion protein-1 promotes liver inflammation and drives hepatic fibrosis

Weston, Chris J.; Shepherd, Emma L.; Claridge, Lee C; Rantakari, Pia; Curbishley, Stuart M.; Tomlinson, Jeremy W.; Hübscher, Stefan G.; Reynolds, Gary; Aalto, Kristiina; Anstee, Quentin M.; Jalkanen, Sirpa; Salmi, Marko; Smith, David J.; Day, Christopher P.; Adams, David H.

doi:10.1172/jci73722

Cited by 188 publications

(226 citation statements)

References 69 publications

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“…The 8-wk-old mice were injected twice weekly for 8 wk with either CCl 4 (1.0 mL/kg CCl 4 diluted 1:3 in mineral oil; Sigma-Aldrich) or a mineral oil vehicle control. Animals were killed 72 h after the final dose of CCl 4 (27) or after a 4-wk recovery period. MCD diet.…”

Section: Methodsmentioning

confidence: 99%

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Stabilin-1 expression defines a subset of macrophages that mediate tissue homeostasis and prevent fibrosis in chronic liver injury

Rantakari

Patten

Valtonen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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104

108

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Macrophages are key regulators of fibrosis development and resolution. Elucidating the mechanisms by which they mediate this process is crucial for establishing their therapeutic potential. Here, we use experimental models of liver fibrosis to show that deficiency of the scavenger receptor, stabilin-1, exacerbates fibrosis and delays resolution during the recovery phase. We detected a subset of stabilin-1 + macrophages that were induced at sites of cellular injury close to the hepatic scar in mouse models of liver fibrosis and in human liver disease. Stabilin-1 deficiency abrogated malondialdehyde-LDL (MDA-LDL) uptake by hepatic macrophages and was associated with excess collagen III deposition. Mechanistically, the lack of stabilin-1 led to elevated intrahepatic levels of the profibrogenic chemokine CCL3 and an increase in GFAP + fibrogenic cells. Stabilin-1 −/− macrophages demonstrated a proinflammatory phenotype during liver injury and the normal induction of Ly6C lo monocytes during resolution was absent in stabilin-1 knockouts leading to persistence of fibrosis. Human stabilin-1 + monocytes efficiently internalized MDA-LDL and this suppressed their ability to secrete CCL3, suggesting that loss of stabilin-1 removes a brake to CCL3 secretion. Experiments with cell-lineage-specific knockouts revealed that stabilin-1 expression in myeloid cells is required for the induction of this subset of macrophages and that increased fibrosis occurs in their absence. This study demonstrates a previously unidentified regulatory pathway in fibrogenesis in which a macrophage scavenger receptor protects against organ fibrosis by removing fibrogenic products of lipid peroxidation. Thus, stabilin-1 + macrophages shape the tissue microenvironment during liver injury and healing.stabilin-1 | liver | fibrosis | macrophages | CCL3

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Section: Methodsmentioning

confidence: 99%

“…Mice were fed an MCD diet (Harlan Laboratories, TD90262) for 6 wk ad libitum. Control animals received normal chow for 6 wk (27). For statistical analysis, see SI Appendix, SI Methods.…”

Section: Methodsmentioning

confidence: 99%

Stabilin-1 expression defines a subset of macrophages that mediate tissue homeostasis and prevent fibrosis in chronic liver injury

Rantakari

Patten

Valtonen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

104

108

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“…+ T and CD4 + T lymphocytes are recruited within the liver in ALD and NAFLD and that T lymphocytes are associated with the prolonging of intralobular inflammation, piecemeal necrosis, and septal fibrosis (42)(43)(44)(45). In additional, Th cells, and especially the conventional Th1 and Th2 subtypes, also play a key role in fibrosis.…”

Section: + T Cells Depending On the Different Functions Of T Cells Imentioning

confidence: 99%

Key role of liver sinusoidal endothelial cells in liver fibrosis

Zou

Zhong

2017

BST

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“…A recent study has elegantly shown that hepatic VAP-1 expression is increased in patients with chronic liver disease and that serum VAP-1 levels are elevated in patients with NAFLD compared to those in control individuals. In murine hepatic injury models, the absence or blockade of functional VAP-1 reduced inflammatory cell recruitment to the liver and attenuated hepatic fibrosis [69]. Moreover, liver disease was reduced in animals expressing a catalytically inactive form of VAP-1, implicating enzyme activity in disease pathogenesis [69].…”

Section: Research Agendamentioning

confidence: 99%

Evidence that non-alcoholic fatty liver disease and polycystic ovary syndrome are associated by necessity rather than chance: a novel hepato-ovarian axis?

2015

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Increasing evidence suggests that non-alcoholic fatty liver disease (NAFLD) and polycystic ovary syndrome (PCOS) are associated with obesity, insulin resistance, metabolic syndrome, cardiovascular disease, cirrhosis, and liver tumors. On these grounds, we have hypothesized that NAFLD and PCOS occur more frequently than expected by chance alone. We have tested this hypothesis by reviewing the clinical and biological evidence that supports a significant association between NAFLD and PCOS. PubMed was extensively searched for articles published through March 2015 using the keywords "nonalcoholic fatty liver disease" or "fatty liver" combined with "PCOS." Several cross-sectional and case-control studies have consistently demonstrated that the prevalence of NAFLD is remarkably increased in young women with PCOS, independent of overweight/obesity and other coexisting metabolic syndrome features, and that these women are more likely to have the more severe forms of NAFLD (non-alcoholic steatohepatitis, advanced fibrosis, and cirrhosis). Accumulating evidence suggests that NAFLD, especially its necro-inflammatory form, may exacerbate hepatic and systemic insulin resistance and releases multiple pro-inflammatory, pro-coagulant, and pro-fibrogenic mediators that may play important roles in the pathophysiology of PCOS. These findings call for more active and systematic search for NAFLD among women with PCOS. Conversely, gastroenterologists/hepatologists need to be aware of the presence of PCOS among female patients with NAFLD and compatible clinical features. Finally, all these patients should undergo regular follow-up not only for liver-related complications but also for cardio-metabolic diseases.

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Vascular adhesion protein-1 promotes liver inflammation and drives hepatic fibrosis

Cited by 188 publications

References 69 publications

Stabilin-1 expression defines a subset of macrophages that mediate tissue homeostasis and prevent fibrosis in chronic liver injury

Stabilin-1 expression defines a subset of macrophages that mediate tissue homeostasis and prevent fibrosis in chronic liver injury

Key role of liver sinusoidal endothelial cells in liver fibrosis

Evidence that non-alcoholic fatty liver disease and polycystic ovary syndrome are associated by necessity rather than chance: a novel hepato-ovarian axis?

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