We thank Dr. Anna Alisi and her colleagues for their interest in our recent study. We agree that the mechanism underlying the antisteatotic effects of all-trans-retinoic acid (ATRA) is not simple and may involve several pathways.
Previous studies have demonstrated that the constitutive activation of AKT in pten knockout or pik3ca transgenic mice resulted in better glucose tolerance than their wildtype counterparts, despite severe steatosis,[1, 2] while akt2 knockout induced hyperglycemia, but alleviated steatosis in ob/ob mice. Because ATRA increased (although not significantly) AKT phosphorylation (Fig. 1) and decreased the hepatic lipid content in mice that were fed a high-fat, high-fructose (HFHFr) diet, the involvement of phosphatase and tensin homolog (PTEN) in the mode of action of ATRA remains to be clarified.
We did not investigate PTEN expression but AKT phosphorylation was significantly higher in the HFHFr group and these results are consistent with the findings of Dr. Anna Alisi indicating that a high fructose-enriched diet could have inhibited PTEN activity. However, ATRA induced more intense AKT phosphorylation than that caused by the HFHFr diet, which suggests a mechanism different from that proposed by Dr. Anna Alisi. In fact, it has been reported that AKT phosphorylation is regulated by many molecules other than PTEN. At the moment, we lack sufficient data to determine whether PTEN activity regulation by ATRA affects the anti-insulin action in these models.
It is possible that ATRA may regulate lipogenesis, partly by impairing insulin-induced AKT phosphorylation by PTEN. In addition, we hypothesize that the antisteatotic effects of ATRA may involve the up-regulation of the lipolytic transcription factors peroxisome proliferator-activated receptor α (PPARα) and PPARβ, with concomitant downregulation of the lipogenic transcription factors PPARγ and sterol regulatory element-binding protein 1.
Insulin resistance causes complex metabolic abnormalities and it has been suggested that the lipogenic effect of insulin is even active in patients with nonalcoholic fatty acid patients. Therefore, further studies are necessary to clarify the precise mechanisms underlying the antisteatotic effects of ATRA.
HIROYUKI TSUCHIYA, PH.D.1
KENTARO KOGURE, PH.D.1
GOSHI SHIOTA, M.D., PH.D.2
1Department of Biophysical Chemistry, Kyoto Pharmaceutical University, Kyoto, Japan
2Department of Genetic Medicine and Regenerative Therapeutics, Graduate School of Medicine, Tottori University, Yonago, Japan