Adipocyte-specific expression of a retinoic acid receptor α dominant negative form causes glucose intolerance and hepatic steatosis in mice

Lee, Seung‐Ah; Jiang, Hongfeng; Feranil, Jun B.; Brun, Pierre‐Jacques; Blaner, William S.

doi:10.1016/j.bbrc.2019.05.075

Cited by 6 publications

(7 citation statements)

References 32 publications

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“…Activation of RARs by AtRA promotes perivascular adipose tissue browning and adiponectin production in Apoe -/- mice [ 28 ]. While adipocyte-specific expression of dominant-negative RAR α causes glucose intolerance and hepatic steatosis in mice [ 31 ]. Nonetheless, how adipocyte RAR α regulates lipid metabolism is not well understood.…”

Section: Discussionmentioning

confidence: 99%

Retinoic Acid Receptor Alpha (RARα) in Macrophages Protects from Diet-Induced Atherosclerosis in Mice

Bawa

Gopoju

et al. 2022

Cells

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Retinoic acid signaling plays an important role in regulating lipid metabolism and inflammation. However, the role of retinoic acid receptor alpha (RARα) in atherosclerosis remains to be determined. In the current study, we investigated the role of macrophage RARα in the development of atherosclerosis. Macrophages isolated from myeloid-specific Rarα-/- (RarαMac-/-) mice showed increased lipid accumulation and inflammation and reduced cholesterol efflux compared to Rarαfl/fl (control) mice. All-trans retinoic acid (AtRA) induced ATP-binding cassette subfamily A member 1 (Abca1) and Abcg1 expression and cholesterol efflux in both RarαMac-/- mice and Rarαfl/fl mice. In Ldlr-/- mice, myeloid ablation of RARα significantly reduced macrophage Abca1 and Abcg1 expression and cholesterol efflux, induced inflammatory genes, and aggravated Western diet-induced atherosclerosis. Our data demonstrate that macrophage RARα protects against atherosclerosis, likely via inducing cholesterol efflux and inhibiting inflammation.

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Section: Discussionmentioning

confidence: 99%

Retinoic Acid Receptor Alpha (RARα) in Macrophages Protects from Diet-Induced Atherosclerosis in Mice

Bawa

Gopoju

et al. 2022

Cells

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“…To address the importance of cell-specific ATRA signaling for the survival during ALI, a mouse model with ablated Rar signaling in ECs (EC-Rardn mice) was generated using an approach and mice we previously employed in our lab in other published studies 91 , 92 . To generate EC-Rardn mice, a mouse line harboring a transgene encoding dominant/negative retinoic acid receptor-α403 (Rardn) mutant protein ( Rardn fl/fl mice 91 , 92 ) was crossed with mice expressing Cre-recombinase (Cre) under the control of a tamoxifen-inducible EC-specific vascular endothelial cadherin ( VE-Cad/Cdh5 ) promotor (EC-CreER T2 mice 93 ). Rardn expression suppresses transcription of all three Rars, thus leading to the near-complete ablation of ATRA signaling 94 , 95 .…”

Section: Resultsmentioning

confidence: 99%

Retinoids stored locally in the lung are required to attenuate the severity of acute lung injury in male mice

et al. 2023

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Retinoids are potent transcriptional regulators that act in regulating cell proliferation, differentiation, and other cellular processes. We carried out studies in male mice to establish the importance of local cellular retinoid stores within the lung alveolus for maintaining its health in the face of an acute inflammatory challenge induced by intranasal instillation of lipopolysaccharide. We also undertook single cell RNA sequencing and bioinformatic analyses to identify roles for different alveolar cell populations involved in mediating these retinoid-dependent responses. Here we show that local retinoid stores and uncompromised metabolism and signaling within the lung are required to lessen the severity of an acute inflammatory challenge. Unexpectedly, our data also establish that alveolar cells other than lipofibroblasts, specifically microvascular endothelial and alveolar epithelial cells, are able to take up lipoprotein-transported retinoid and to accumulate cellular retinoid stores that are directly used to respond to an acute inflammatory challenge.

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“…This characteristic expression pattern may indicate specific functions for RAR isoforms in liver and WAT biology. Lee et al have shown that altered RAR signalling in adipocytes resulted in a significant decrease in all- trans -retinoic acid levels in visceral adipose tissues as well as in the liver tissue [ 20 ]. In this study, it is evident that RA protected mice from NAFLD.…”

Section: Discussionmentioning

confidence: 99%

Adipose tissue plays a major role in retinoic acid-mediated metabolic homoeostasis

et al. 2021

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Retinoic acid (RA), a bioactive metabolite of vitamin A, has shown therapeutic effects in liver disease, and its effect in improving non-alcoholic fatty liver disease (NAFLD) is associated with the inhibition of adipogenesis in the white adipose tissue (WAT) and fatty acid oxidation induction in the liver. However, the major target organ of RA is unknown. We performed chronic administration of RA in high-fat diet (HFD)-induced NAFLD mice. Further, hepatic and adipose cells were used to study the direct effect of RA on lipid metabolism. In addition, qRT-PCR was performed to examine differential gene expression in mouse adipose tissue. RA administration ameliorated NAFLD in HFD-induced obese mice and increased mouse energy expenditure. Although RA had therapeutic effects on liver histology and lipid accumulation, it did not directly affect lipid metabolism in HepG2 cells. In contrast, RA reduced the weight of several adipose tissues and improved lipid accumulation in OP9 cells. In addition, RA upregulated genes responsible for fatty acid oxidation and thermogenesis in three different WATs. Our work suggests that the liver may not be the main target organ of RA during NAFLD treatment. WAT browning induced by RA may be the primary contributor towards the amelioration of NAFLD in HFD-induced obese mice.

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Adipocyte-specific expression of a retinoic acid receptor α dominant negative form causes glucose intolerance and hepatic steatosis in mice

Cited by 6 publications

References 32 publications

Retinoic Acid Receptor Alpha (RARα) in Macrophages Protects from Diet-Induced Atherosclerosis in Mice

Retinoic Acid Receptor Alpha (RARα) in Macrophages Protects from Diet-Induced Atherosclerosis in Mice

Retinoids stored locally in the lung are required to attenuate the severity of acute lung injury in male mice

Adipose tissue plays a major role in retinoic acid-mediated metabolic homoeostasis

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