重篤な肝疾患の治療薬となる抗体候補(Antibody candidate for treating serious liver disease)

2023-02-03 スウェーデン王国・カロリンスカ研究所(KI)

<関連情報>

• https://news.ki.se/antibody-candidate-for-treating-serious-liver-disease
• https://www.journal-of-hepatology.eu/article/S0168-8278(23)00026-0/fulltext

VEGF-Bシグナル阻害による白色脂肪組織での脂肪分解を標的とした非アルコール性脂肪肝疾患発症抑制効果 Inhibition of VEGF-B signaling prevents non-alcoholic fatty liver disease development by targeting lipolysis in the white adipose tissue

Annelie Falkevall,Annika Mehlem,Erika Folestad,Frank Chenfei Ning,Óscar Osorio-Conles,Rosa Radmann,Ana de Hollanda,Samuel D. Wright,Pierre Scotney,Andrew Nash,Ulf Eriksson
Journal of Hepatology  Published:January 26, 2023
DOI:https://doi.org/10.1016/j.jhep.2023.01.014

Highlights

•Inhibition of VEGF-B signaling reduced hepatosteatosis and NAFLD in diabetic mice

•VEGF-B-regulated lipolysis in the white adipose tissue contributed to NAFLD

•The beneficial effect was due to re-sensitizing adipocytes to insulin signaling

•VEGF-B signaling was up-regulated in clinical WAT biopsies from NAFLD subjects

•VEGF-B antagonism may be a therapeutic strategy for the treatment of NAFLD

Abstract

Background & Aims
Hepatosteatosis is a hallmark of Non-alcoholic fatty liver disease (NAFLD), a common co-morbidity in Type 2 diabetes (T2DM). The pathogenesis of NAFLD is complex and involves the crosstalk between the liver and the white adipose tissues (WAT). Vascular Endothelial Growth Factor B (VEGF-B) has been described to control tissue lipid accumulation by regulating the transport properties of the vasculature. The role of VEGF-B-signaling and the contribution to hepatosteatosis and NAFLD in T2DM is currently not understood.

Methods
C57BL/6J mice treated with a neutralizing antibody against VEGF-B, or mice with adipocyte-specific overexpression- or under-expression of VEGF-B (Adipoq^Cre+/VEGF-B^TG/+ mice and Adipoq^Cre+/Vegfb^fl/+mice) were subjected to a 6-month high-fat diet (HFD), or chow-diet, whereafter NAFLD development was assessed. WAT biopsies from patients with obesity and NAFLD in a pre-existing clinical cohort (n=24 patients with NAFLD and n=24 without NAFLD) were analysed for VEGF-B expression and correlated to clinicopathological features.

Results
Pharmacological inhibition of VEGF-B signaling in diabetic mice reduced hepatosteatosis and NAFLD by blocking WAT lipolysis. Mechanistically we show, by using HFD-fed Adipoq^Cre+/VEGF-B^TG/+ mice and HFD-fed Adipoq^Cre+/Vegfb ^fl/+mice, that inhibition of VEGF-B signaling targets lipolysis in adipocytes. Reducing VEGF-B signaling ameliorated NAFLD by decreasing WAT inflammation, resolving WAT insulin resistance, and lower the activity of the hormone sensitive lipase. Analyses of human WAT biopsies from NAFLD subjects supported that the VEGF-B signaling pathway contributes to NAFLD development. VEGF-B expression levels in adipocytes from two WAT depots correlated with development of dysfunctional WAT and NAFLD in human subjects.

Conclusions
Taken together, our data from mouse models and human subjects suggest that VEGF-B antagonism may represent an approach to combat NAFLD by targeting hepatosteatosis through suppression of lipolysis.

Impact and implications
NAFLD is a common co-morbidity in type 2 diabetes mellitus (T2DM), and the global prevalence is between 25-29 %. There are currently no approved medicines for treating NAFLD, and given the enormous proportions of the ongoing diabetes epidemics, there is an urgent need to identify new treatment options. Our work suggest that VEGF-B antagonism may represent an approach to combat NAFLD by targeting hepatosteatosis through suppression of lipolysis. The neutralizing anti-VEGF-B antibody, which was used in this study, has already entered clinical trials in diabetic patients. Therefore, we believe that our results are of great general interest to a broad audience, including patients and patient organizations, the medical community, academia, the life science industry and the public.