Retinoids Counteract Insulin Resistance And Liver Steatosis: What's the Potential Mechanism?

We read with great interest a recent article published in this journal by Tsuchiya et al.1 In this study the authors investigated all-trans-retinoic acid (ATRA) effects in different mouse models to explore its anti-insulin resistance activities and inspected mechanisms engaged in this condition and associated hepato-metabolic disorders. Tsuchiya et al.1 found that ATRA improved insulin sensitivity and activated the leptin signaling pathway in C57BL/6J mice fed a high-fat, high-fructose (HFHFr) diet and in genetically insulin resistant KK-Ay mice. Furthermore, ATRA retrieved metabolic derangements in both models, counteracting liver steatosis and ballooning in HFHFr animals. The authors suggested a possible interaction between the leptin-mediated pathway and retinoic acid receptor (RAR)-mediated transcriptional regulation to explain ATRA-dependent insulin sensitivity improvement. However, the role of the RAR/leptin network in regulating the antisteatotic effect of ATRA remains to be verified. We recently reported that high fructose-enriched diets may promote phosphatase and tensin homolog (PTEN) phosphorylation/inactivation inducing nonalcoholic fatty liver disease (NAFLD).2 Therefore, we hypothesized that retinoids might have a positive effect on liver steatosis affecting PTEN signaling, a complex PI3K/AKT regulatory pathway involved in the control of hepatic glucose and lipid metabolism.3, 4 The role of PTEN in mediating the antisteatotic effect of ATRA is supported by our preliminary data. We studied the effect of ATRA in an in vitro model of hepatic steatosis using HepG2 cells supplemented with combined oleic acid (OA) and palmitic acid (PA) (molar ratio 2:1) at 1 mM final concentration. As shown in Fig. 1A, after 24 hours OA/PA supplementation induced an increase of intracellular lipid accumulation that was significantly reduced by treatment with 5 μM ATRA for 5 hours. Moreover, neither OA/PA nor ATRA treatments influenced cell viability (Fig. 1B). Importantly, ATRA reduced fatty acid-dependent PTEN phosphorylation/inactivation (Fig. 1C). ATRA effects on HepG2 cells treated with OA/PA. HepG2 cells were treated for 24 hours with normal medium (NM) alone or with control vehicle (MetOH), or 1 mM OA/PA (OA/PA). NM and OA/PA cells were then exposed to 5 μM ATRA for 5 hours. (A) Absorbance of extracted Oil Red O-stained lipids. (B) Cell viability by XTT assay. (C) Western blotting of PTEN and phosphoPTEN Ser380. Actin was used as a loading control. *P < 0.05; ***P < 0.001. All these findings suggest that retinoids are potential appropriate therapeutic agents to resolve both metabolic alterations and liver-damage triggered by genetically or a diet-induced insulin resistant state. Tsuchiya et al.1 demonstrated that the leptin pathway may be crucial for the anti-insulin resistance action of ATRA, and we proposed PTEN as a mediator of its antisteatotic effect. However, due to the multiple interactions between retinoids and different signaling networks, further studies are necessary to identify mechanisms involved in ATRA-mediated transcriptional regulation of relevant metabolic and liver genes. NADIA PANERA, SC.B. SARA CECCARELLI, PH.D. CRISTIANO DE STEFANIS, SC.B. VALERIO NOBILI, M.D. ANNA ALISI, PH.D. Liver Research Unit, "Bambino Gesú" Children's Hospital, IRCCS, Rome, Italy