PMID- 36717026 OWN - NLM STAT- MEDLINE DCOM- 20230418 LR - 20231220 IS - 1600-0641 (Electronic) IS - 0168-8278 (Linking) VI - 78 IP - 5 DP - 2023 May TI - Inhibition of VEGF-B signaling prevents non-alcoholic fatty liver disease development by targeting lipolysis in the white adipose tissue. PG - 901-913 LID - S0168-8278(23)00026-0 [pii] LID - 10.1016/j.jhep.2023.01.014 [doi] AB - BACKGROUND & AIMS: Hepatic steatosis is a hallmark of non-alcoholic fatty liver disease (NAFLD), a common comorbidity in type 2 diabetes mellitus (T2DM). The pathogenesis of NAFLD is complex and involves the crosstalk between the liver and the white adipose tissue (WAT). Vascular endothelial growth factor B (VEGF-B) has been shown to control tissue lipid accumulation by regulating the transport properties of the vasculature. The role of VEGF-B signaling and the contribution to hepatic steatosis and NAFLD in T2DM is currently not understood. METHODS: C57BL/6 J 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. VEGF-B expression was analysed in WAT biopsies from patients with obesity and NAFLD in a pre-existing clinical cohort (n = 24 patients with NAFLD and n = 24 without NAFLD) and correlated to clinicopathological features. RESULTS: Pharmacological inhibition of VEGF-B signaling in diabetic mice reduced hepatic steatosis 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 lowering the activity of the hormone sensitive lipase. Analyses of human WAT biopsies from individuals with NAFLD provided evidence supporting the contribution of VEGF-B signaling to NAFLD development. VEGF-B expression levels in adipocytes from two WAT depots correlated with development of dysfunctional WAT and NAFLD in humans. CONCLUSIONS: Taken together, our data from mouse models and humans suggest that VEGF-B antagonism may represent an approach to combat NAFLD by targeting hepatic steatosis through suppression of lipolysis. IMPACT AND IMPLICATIONS: Non-alcoholic fatty liver disease (NAFLD) is a common comorbidity in type 2 diabetes mellitus (T2DM) and has a global prevalence of between 25-29%. There are currently no approved drugs for NAFLD, and given the scale of the ongoing diabetes epidemics, there is an urgent need to identify new treatment options. Our work suggests that VEGF-B antagonism may represent an approach to combat NAFLD by targeting hepatic steatosis through suppression of lipolysis. The neutralizing anti-VEGF-B antibody, which was used in this study, has already entered clinical trials for patients with diabetes. 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. CI - Copyright (c) 2023 The Authors. Published by Elsevier B.V. All rights reserved. FAU - Falkevall, Annelie AU - Falkevall A AD - Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. FAU - Mehlem, Annika AU - Mehlem A AD - Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. FAU - Folestad, Erika AU - Folestad E AD - Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. FAU - Ning, Frank Chenfei AU - Ning FC AD - Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. FAU - Osorio-Conles, Oscar AU - Osorio-Conles O AD - Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM), Madrid, Spain. FAU - Radmann, Rosa AU - Radmann R AD - Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. FAU - de Hollanda, Ana AU - de Hollanda A AD - Obesity Unit. Clinical Hospital of Barcelona, Barcelona, Spain; Centro de Investigacion Biomedica en Red Fisiopatologia de la Obesidad y Nutricion (CIBEROBN), Madrid, Spain. FAU - Wright, Samuel D AU - Wright SD AD - CSL Behring, King of Prussia, PA, USA. FAU - Scotney, Pierre AU - Scotney P AD - CSL Innovation Pty Ltd, Parkville, Victoria, Australia. FAU - Nash, Andrew AU - Nash A AD - CSL Innovation Pty Ltd, Parkville, Victoria, Australia. FAU - Eriksson, Ulf AU - Eriksson U AD - Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. Electronic address: ulf.pe.eriksson@ki.se. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230127 PL - Netherlands TA - J Hepatol JT - Journal of hepatology JID - 8503886 RN - 0 (Vascular Endothelial Growth Factor B) SB - IM CIN - Hepatobiliary Surg Nutr. 2023 Dec 1;12(6):963-965. PMID: 38115926 MH - Humans MH - Animals MH - Mice MH - *Non-alcoholic Fatty Liver Disease/etiology/prevention & control/metabolism MH - Lipolysis MH - Vascular Endothelial Growth Factor B/metabolism MH - *Diabetes Mellitus, Experimental/metabolism MH - *Diabetes Mellitus, Type 2/complications/metabolism MH - Mice, Inbred C57BL MH - Liver/pathology MH - Adipose Tissue, White/metabolism/pathology MH - Diet, High-Fat/adverse effects MH - Adipose Tissue/metabolism OTO - NOTNLM OT - NAFLD OT - VEGF-B OT - lipid metabolism OT - lipolysis OT - tissue cross talk EDAT- 2023/01/31 06:00 MHDA- 2023/04/18 06:41 CRDT- 2023/01/30 19:28 PHST- 2022/06/23 00:00 [received] PHST- 2022/12/22 00:00 [revised] PHST- 2023/01/13 00:00 [accepted] PHST- 2023/04/18 06:41 [medline] PHST- 2023/01/31 06:00 [pubmed] PHST- 2023/01/30 19:28 [entrez] AID - S0168-8278(23)00026-0 [pii] AID - 10.1016/j.jhep.2023.01.014 [doi] PST - ppublish SO - J Hepatol. 2023 May;78(5):901-913. doi: 10.1016/j.jhep.2023.01.014. Epub 2023 Jan 27.