Bone morphogenetic protein 8B promotes the progression of non-alcoholic steatohepatitis

被引：48

作者：

Vacca, Michele ^{[1
,2
,3
]}

Leslie, Jack ^{[4
]}

Virtue, Samuel ^{[1
]}

Lam, Brian Y. H. ^{[5
]}

Govaere, Olivier ^{[6
]}

Tiniakos, Dina ^{[6
,7
]}

Snow, Sophie ^{[8
]}

Davies, Susan ^{[9
]}

Petkevicius, Kasparas ^{[1
]}

Tong, Zhen ^{[10
]}

Peirce, Vivian ^{[1
]}

Nielsen, Mette Juul ^{[11
]}

Ament, Zsuzsanna ^{[2
,3
]}

Li, Wei ^{[10
]}

Kostrzewski, Tomasz ^{[8
]}

Leeming, Diana Julie ^{[11
]}

Ratziu, Vlad ^{[12
]}

Allison, Michael E. D. ^{[9
]}

Anstee, Quentin M. ^{[6
,13
]}

Griffin, Julian L. ^{[2
,3
,14
]}

Oakley, Fiona ^{[4
]}

Vidal-Puig, Antonio ^{[1
,15
,16
]}

机构：

[1] Univ Cambridge, WT MRC Inst Metab Sci, MRC Metab Dis Unit, TVP Lab,Metab Res Labs, Cambridge, England

[2] Univ Cambridge, Dept Biochem, Cambridge, England

[3] Univ Cambridge, Cambridge Syst Biol Ctr, Cambridge, England

[4] Newcastle Univ, Fac Med Sci, Biosci Inst, Newcastle Fibrosis Res Grp, Newcastle Upon Tyne, Tyne & Wear, England

[5] Univ Cambridge, WT MRC Inst Metab Sci, Yeo Grp & Genom & Transcript Core, Cambridge, England

[6] Newcastle Univ, Fac Med Sci, Translat & Clin Res Inst, Newcastle Upon Tyne, Tyne & Wear, England

[7] Natl & Kapodistrian Univ Athens, Aretaie Hosp, Med Sch, Dept Pathol, Athens, Greece

[8] CN Bio Innovat Ltd, Cambridge, England

[9] Cambridge Univ Hosp, Cambridge Biomed Res Ctr, Dept Med, Liver Unit, Cambridge, England

[10] Univ Cambridge, Dept Med, Cambridge, England

[11] Nordic Biosci AS, Herlev, Denmark

[12] Sorbonne Univ, Inst Cardiometab & Nutr ICAN, Hop Pitie Salpetriere, Paris, France

[13] Newcastle Tyne Hosp NHS Fdn Trust, Newcastle NIHR Biomed Res Ctr, Newcastle Upon Tyne, Tyne & Wear, England

[14] Imperial Coll London, Dept Metab Digest & Reprod, Syst Med, Biomol Med, London, England

[15] Welcome Trust Sanger Inst, Hinxton, England

[16] Cambridge Univ Nanjing Ctr Technol & Innovat, Nanjing, Peoples R China

来源：

NATURE METABOLISM | 2020年 / 2卷 / 06期

基金：

英国医学研究理事会;

关键词：

LIVER-INJURY; GENE-EXPRESSION; SCORING SYSTEM; FATTY-ACID; FIBROSIS; BMP8B; OSTEOPROTEGERIN; GROWTH; BLOOD; MODEL;

D O I：

10.1038/s42255-020-0214-9

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Non-alcoholic steatohepatitis (NASH) is characterized by lipotoxicity, inflammation and fibrosis, ultimately leading to end-stage liver disease. The molecular mechanisms promoting NASH are poorly understood, and treatment options are limited. Here, we demonstrate that hepatic expression of bone morphogenetic protein 8B (BMP8B), a member of the transforming growth factor beta (TGF beta)-BMP superfamily, increases proportionally to disease stage in people and animal models with NASH. BMP8B signals via both SMAD2/3 and SMAD1/5/9 branches of the TGF beta-BMP pathway in hepatic stellate cells (HSCs), promoting their proinflammatory phenotype. In vivo, the absence of BMP8B prevents HSC activation, reduces inflammation and affects the wound-healing responses, thereby limiting NASH progression. Evidence is featured in primary human 3D microtissues modelling NASH, when challenged with recombinant BMP8. Our data show that BMP8B is a major contributor to NASH progression. Owing to the near absence of BMP8B in healthy livers, inhibition of BMP8B may represent a promising new therapeutic avenue for NASH treatment.

引用

页码：514 / +

页数：26

共 63 条

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