Inhibition of VEGF-B signaling prevents non-alcoholic fatty liver disease development by targeting lipolysis in the white adipose tissue

Falkevall, Annelie; Mehlem, Annika; Folestad, Erika; Ning, Frank Chenfei; Osorio-Conles, Óscar; Radmann, Rosa; Hollanda, Ana de; Wright, Samuel D.; Scotney, Pierre; Nash, Andrew D.; Eriksson, Ulf

doi:10.1016/j.jhep.2023.01.014

Cited by 28 publications

(15 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…4D), and also modestly induced adipose tissue lipolysis reflected by an increase in plasma non-esterified fatty acid (NEFA) concentrations (Extended Data Fig. 4H), as has been shown previously 42 .…”

supporting

confidence: 81%

FGF-21 Conducts a Liver-Brain-Kidney Axis to Promote Renal Cell Carcinoma

Zhang

Zhu

et al. 2023

Preprint

View full text Add to dashboard Cite

Metabolic homeostasis is one of the most exquisitely tuned systems in mammalian physiology. Metabolic homeostasis requires multiple redundant systems to cooperate to maintain blood glucose concentrations in a narrow range, despite a multitude of physiological and pathophysiological pressures. Cancer is one of the canonical pathophysiological settings in which metabolism plays a key role. In this study, we utilized REnal Gluconeogenesis Analytical Leads (REGAL), a liquid chromatography-mass spectrometry/mass spectrometry-based stable isotope tracer method that we developed to show that in conditions of metabolic stress, the fasting hepatokine fibroblast growth factor-21 (FGF-21) coordinates a liver-brain-kidney axis to promote renal gluconeogenesis. FGF-21 promotes renal gluconeogenesis by enhancing beta-adrenergic receptor (Adrb2)-driven, adipose triglyceride lipase (ATGL)-mediated intrarenal lipolysis. Further, we show that this liver-brain-kidney axis promotes gluconeogenesis in the renal parenchyma in mice and humans with renal cell carcinoma (RCC). This increased gluconeogenesis is, in turn, associated with accelerated RCC progression. We identify Adrb2 blockade as a new class of therapy for RCC in mice, with confirmatory data in human patients. In summary, these data reveal a new metabolic function of FGF-21 in driving renal gluconeogenesis, and demonstrate that inhibition of renal gluconeogenesis by FGF-21 antagonism deserves attention as a new therapeutic approach to RCC.

show abstract

supporting

confidence: 81%

FGF-21 Conducts a Liver-Brain-Kidney Axis to Promote Renal Cell Carcinoma

Zhang

Zhu

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…While VEGFR1 is necessary for VEGF-B activation of mTORC1, neuropilin-1 (NRP1) is also required for fatty acid transport across endothelial cells but it is unclear how this co-receptor may be involved in the signaling cascade 8,[30][31][32][33] . Like skeletal muscle, heart and adipose tissues, VEGF-B expression is elevated in human disease, including increased expression within tumors and cell lines [10][11][12]34 . Still, its role in cancer has been largely unknown, which may be somewhat attributed to both pro-and anti-angiogenic properties described for VEGF-B [13][14][15] .…”

Section: Discussionmentioning

confidence: 99%

Regulation of fatty acid delivery to metastases by tumor endothelium

Edwards,

Wang,

Song

et al. 2024

Preprint

View full text Add to dashboard Cite

Tumor metastasis, the main cause of death in cancer patients, requires outgrowth of tumor cells after their dissemination and residence in microscopic niches. Nutrient sufficiency is a determinant of such outgrowth. Fatty acids (FA) can be metabolized by cancer cells for their energetic and anabolic needs but impair the cytotoxicity of T cells in the tumor microenvironment (TME), thereby supporting metastatic progression. However, despite the important role of FA in metastatic outgrowth, the regulation of intratumoral FA is poorly understood. In this report, we show that tumor endothelium actively promotes tumor growth and restricts anti-tumor cytolysis by transferring FA into developing metastatic tumors. This process uses transendothelial fatty acid transport via endosome cargo trafficking in a mechanism that requires mTORC1 activity. Thus, tumor burden was significantly reduced upon endothelial-specific targeted deletion of Raptor, a unique component of the mTORC1 complex (RptorECKO). In vivo trafficking of a fluorescent palmitic acid analog to tumor cells and T cells was reduced in RptorECKO lung metastatic tumors, which correlated with improved markers of T cell cytotoxicity. Combination of anti-PD1 with RAD001/everolimus, at a low dose that selectively inhibits mTORC1 in endothelial cells, impaired FA uptake in T cells and reduced metastatic disease, corresponding to improved anti-tumor immunity. These findings describe a novel mechanism of transendothelial fatty acid transfer into the TME during metastatic outgrowth and highlight a target for future development of therapeutic strategies.

show abstract

“…Studies have shown that increased expression of inflammatory genes and macrophage activation in visceral and subcutaneous adipose tissue of NAFLD patients correlate with progression of simple steatosis of fibrosis [ 61 ]. Furthermore, Falkevall et al [ 62 ] utilized a vascular endothelial growth factor-B (VEGF-B) antagonist to inhibit the progression of white adipose tissue inflammation, revolved insulin resistance in white adipose tissue, and reduced hormone-sensitive adiponectin activity, resulting in improvement of NAFLD. To sum up, adipose tissue plays an important role in the liver in recent years, which is expected to provide a new target for the diagnosis and treatment of NAFLD caused by abnormal metabolism of adipose tissue.…”

Section: The Role Of Adipose Tissue In Metabolic Diseasesmentioning

confidence: 99%

Adipose Tissue-Derived Extracellular Vesicles: A Promising Biomarker and Therapeutic Strategy for Metabolic Disorders

Liu,

Zhao

et al. 2023

Stem Cells International

View full text Add to dashboard Cite

Adipose tissue plays an important role in systemic energy metabolism, and its dysfunction can lead to severe metabolic disorders. Various cells in adipose tissue communicate with each other to maintain metabolic homeostasis. Extracellular vesicles (EVs) are recognized as novel medium for remote intercellular communication by transferring various bioactive molecules from parental cells to distant target cells. Increasing evidence suggests that the endocrine functions of adipose tissue and even the metabolic homeostasis are largely affected by different cell-derived EVs, such as insulin signaling, lipolysis, and metabolically triggered inflammation regulations. Here, we provide an overview focused on the role of EVs released by different cell types of adipose tissue in metabolic diseases and their possible molecular mechanisms and highlight the potential applications of EVs as biomarkers and therapeutic targets. Moreover, the current EVs-based therapeutic strategies have also been discussed. This trial is registered with NCT05475418.

show abstract

Inhibition of VEGF-B signaling prevents non-alcoholic fatty liver disease development by targeting lipolysis in the white adipose tissue

Cited by 28 publications

References 24 publications

FGF-21 Conducts a Liver-Brain-Kidney Axis to Promote Renal Cell Carcinoma

FGF-21 Conducts a Liver-Brain-Kidney Axis to Promote Renal Cell Carcinoma

Regulation of fatty acid delivery to metastases by tumor endothelium

Adipose Tissue-Derived Extracellular Vesicles: A Promising Biomarker and Therapeutic Strategy for Metabolic Disorders

Contact Info

Product

Resources

About