Obesity negatively affects multiple metabolic pathways, but little is known about the impact of obesity on vitamin A (VA)[retinol (ROL)], a nutrient that regulates expression of genes in numerous pathways essential for human development and health. We demonstrate that obese mice, generated from a high fat diet (HFD) or by genetic mutations (i.e., ob/ob; db/db), have greatly reduced ROL levels in multiple organs, including liver, lungs, pancreas, and kidneys, even though their diets have adequate VA. However, obese mice exhibit elevated serum VA. Organs from obese mice show impaired VA transcriptional signaling, including reductions in retinoic acid receptor (RARα, RARβ2 and RARγ) mRNAs and lower intracellular ROL binding protein Crbp1 (RBP1) levels in VA-storing stellate cells. Reductions in organ VA signaling in obese mice correlate with increasing adiposity and fatty liver (steatosis), while with weight loss VA levels and signaling normalize. Consistent with our findings in obese mice, we show that increasing severity of fatty liver disease in humans correlates with reductions in hepatic VA, VA transcriptional signaling, and Crbp1 levels in VA storing stellate cells. Thus, obesity causes a “silent” VA deficiency marked by reductions in VA levels and signaling in multiple organs, but not detected by serum VA.

Background:Little is known about vitamin A (VA) regulation of pancreatic endocrine mass in adults. Results: Decreased pancreatic VA causes increased ␣-cell to ␤-cell mass ratios, hyperglycemia, and hyperglucagonemia. Reintroducing dietary VA restores normoglycemia and ␣-cell to ␤-cell mass. Conclusion: VA is essential for maintenance of ␤-cell functions in adult pancreas. Significance: VA therapies may potentially prevent ␤-cell apoptosis and loss in diabetes.

Aims Retinoids (vitamin A (retinol), and structurally related molecules) possess metabolic modulating properties, prompting new interest in their role in the treatment of diabetes and fatty liver disease, but little is known about the effects of specific retinoic acid receptor (RAR) agonists in these diseases. Materials and Methods Synthetic agonists for retinoic acid receptor RARβ2 were administered to wild type (wt) mice in a model of high fat diet (HFD)-induced type 2 diabetes (T2D) and to ob/ob and db/db mice (genetic models of obesity-associated T2D). Results We demonstrate that administration of synthetic agonists for the retinoic acid receptor RARβ2 to either wild type (wt) mice in a model of high fat diet (HFD)-induced type 2 diabetes (T2D) or to ob/ob and db/db mice (genetic models of obesity-associated T2D) reduces hyperglycemia, peripheral insulin resistance, and body weight. Furthermore, RARβ2 agonists dramatically reduce steatosis, lipid peroxidation, and oxidative stress in the liver, pancreas, and kidneys of obese, diabetic mice. RARβ2 agonists also lower levels of mRNAs involved in lipogenesis, such as SREBP1 and FASN (fatty acid synthase), and increase mRNAs that mediate mitochondrial fatty acid β-oxidation, such as CPT1α, in these organs. RARβ2 agonists lower triglyceride levels in these organs, and in muscle. Conclusions Collectively, our data show that orally active, rapidly acting, high affinity pharmacological agonists for RARβ2 improve the diabetic phenotype while reducing lipid levels in key insulin target tissues. We suggest that RARβ2 agonists should be useful drugs for T2D therapy and for treatment of hepatic steatosis.

The 2020 global outbreak of the novel coronavirus (SARS‐CoV‐2 or COVID‐19) is a serious threat to international health, and thus, there is an urgent need for discovery of novel therapies or use of repurposed drugs that can make a significant impact on slowing the spread of the virus. Type 1 interferons (IFN‐I) are a family cytokines of the early innate immune response to viruses that are being tested against SARS‐CoV‐2. However, coronaviruses similar to SARS‐CoV‐2 can suppress host IFN‐I antiviral responses. Retinoids are a family molecules related to vitamin A that possess robust immune‐modulating properties, including the ability to increase and potentiate the actions of IFN‐I. Therefore, adjuvants such as retinoids, capable of increasing IFN‐I‐mediated antiviral responses, should be tested in combinations of IFN‐I and antiviral drugs in pre‐clinical studies of SARS‐CoV‐2.

Hepatic stellate cells (HSCs) are an important cellular target for the development of novel pharmacological therapies to prevent and treat non-alcoholic fatty liver diseases (NAFLD). Using a high fat diet (HFD) model of NAFLD, we sought to determine if synthetic selective agonists for retinoic acid receptor β2 (RARβ2) and RARγ can mitigate HSC activation and HSC relevant signaling pathways during early stages of NAFLD, before the onset of liver injury. We demonstrate that the highly selective RARβ2 agonist, AC261066, can reduce the activation of HSCs, marked by decreased HSC expression of α-smooth muscle actin (α-SMA), in mice with HFD-induced NAFLD. Livers of HFD-fed mice treated with AC261066 exhibited reduced steatosis, oxidative stress, and expression of pro-inflammatory mediators, such as tumor necrosis factor-alpha (TNFα), interleukin 1β (IL-1β), and monocyte chemotactic protein-1 (MCP-1). Kupffer cell (macrophage) expression of transforming growth factor-β1 (TGF-β1), which plays a critical role in early HSC activation, was markedly reduced in AC261066 treated, HFD-fed mice. In contrast, HFD-fed mice treated with an RARγ agonist (CD1530) showed no decreases in steatosis, HSC activation, or Kupffer cell TGF-β1 levels. In conclusion, our data demonstrate that RARβ2 is an attractive target for development of NAFLD therapies.

Previous gene array data from our laboratory identified the retinoic acid (RA) biosynthesis enzyme aldehyde dehydrogenase 1A3 (ALDH1A3) as a putative androgen‐responsive gene in prostate cancer epithelial cells (LNCaP). In the present study we attempted to identify if any of the three ALDH/RA synthesis enzymes are androgen responsive and how this may affect retinoid‐mediated events in LNCaP cells. We demonstrated that exposure of LNCaP cells to the androgen dihydrotestosterone (DHT) resulted in a five‐fold increase of ALDH1A3 mRNA levels compared to the untreated controls. The mRNA for two other ALDH1A family members, ALDH1A1 and ALDH1A2, were not detected and not induced by DHT in LNCaP cells. Inhibition of androgen receptor (AR) with both the anti‐androgen Casodex and small interfering RNA (siRNA) for AR, support the premise that ALDH1A3 regulation by DHT is mediated by AR. Consistently, DHT‐treated LNCaP cell lysates showed an eight‐fold increase in retinaldehyde‐dependent NAD+ reduction activity compared to controls. Furthermore, treatment of LNCaP cells with all trans‐retinal (RAL) in the presence of DHT resulted in a significant up‐regulation of the RA‐inducible RA metabolizing enzyme CYP26A1 mRNA, a surrogate endpoint for RA bioactivity and metabolism. Taken together, these data suggest that: androgen regulation of the ALDH1A3 gene is via direct action through the AR, and DHT up‐regulation of ALDH1A3 can increase the oxidation of RAL to RA and indirectly affect RA bioactivity and metabolism.

Recent evidence suggests that the liver X receptor (LXR) is a potential anticancer target in prostate carcinoma. There is little characterization, however, of which of the two LXR isoforms, LXRα or LXRβ, regulates the LXRresponsive genes ATP-binding cassette subfamily members A1 (ABCA1) and G1 (ABCG1) in transformed prostatic epithelial cells. In this study, small interfering RNA (siRNA) was used to determine whether LXRα or LXRβ is involved in regulating ABCA1 and ABCG1 mRNA expression in LNCaP and PC-3 cells. Treatment of both cell lines with the synthetic LXR ligand T0901317 and oxysterols: 25-hydroxycholesterol (25HC) and 24(S), 25-epoxycholesterol (24,25EC), resulted in more than a 10-fold increase of ABCA1 and ABCG1 mRNA expression. Transfection of LNCaP cells with siRNA against either LXRβ or LXRα failed to inhibit T0901317 and 25HC-mediated increase of ABCA1 mRNA. siRNA silencing of LXRβ did, however, inhibit ABCA1 mRNA expression in 24,25EC-treated LNCaP cells. In contrast, LXRβ siRNA inhibited T0901317, 25HC, and 24,25EC induction of ABCA1 mRNA in PC-3 cells and ABCG1 mRNA in both LNCaP and PC-3 cells. Additional experiments revealed that T0901317 and 25HC induction of ABCA1 mRNA expression was significantly inhibited by the p38 stress kinase antagonist SB202190 and PKA inhibitor H89. Our study is the first to show that LXRβ, but not LXRα, is the major regulatory isoform of ABCG1 mRNA expression in LNCaP and PC-3 cells. Our study also reveals that ABCA1 gene expression is differentially regulated by synthetic and natural LXR ligands, possibly involving kinase mediated signal transduction.

Vitamin A has a critical role in embryonic development, immunity and the visual cycle. In recent years, evidence has demonstrated that vitamin A can also regulate metabolic pathways implicated in the pathogenesis of obesity and diabetes. This has increased interest in the possible antiobesity and antidiabetic properties of natural and synthetic vitamin A derivatives. However, whether vitamin A deficiency or aberrations in vitamin A metabolism contribute to the pathogenesis of diabetes is not known. This perspective article will review what is currently known and new data regarding the link between vitamin A and the clinical manifestations of common and atypical forms of diabetes.