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Type 2 diabetes (T2D) is often accompanied with an induction of retinaldehyde dehydrogenase 1 (RALDH1 or ALDH1A1) expression and a consequent decrease in hepatic retinaldehyde (Rald) levels. However, the role of hepatic Rald deficiency in T2D progression remains unclear. In this study, we demonstrated that reversing T2D-mediated hepatic Rald deficiency by Rald or citral treatments, or liver-specific Raldh1 silencing substantially lowered fasting glycemia levels, inhibited hepatic glucogenesis, and downregulated phosphoenolpyruvate carboxykinase 1 (PCK1) and glucose-6-phosphatase (G6PC) expression in diabetic db/db mice. Fasting glycemia and Pck1/G6pc mRNA expression levels were strongly negatively correlated with hepatic Rald levels, indicating the involvement of hepatic Rald depletion in T2D deterioration. A similar result that liver-specific Raldh1 silencing improved glucose metabolism was also observed in high-fat diet-fed mice. In primary human hepatocytes and oleic acid-treated HepG2 cells, Rald or Rald + RALDH1 silencing resulted in decreased glucose production and downregulated PCK1/G6PC mRNA and protein expression. Mechanistically, Rald downregulated direct repeat 1-mediated PCK1 and G6PC expression by antagonizing retinoid X receptor α, as confirmed by luciferase reporter assays and molecular docking. These results highlight the link between hepatic Rald deficiency, glucose dyshomeostasis, and the progression of T2D, whilst also suggesting RALDH1 as a potential therapeutic target for T2D.
RESUMEN
Objective To study the effect of retinaldehyde dehydrogenase 2 (Raldh2) on the differentiation of P19 cell to cardiomyocyte-like cells and explore the potential mechanism.Methods A miRNA expression plasmid specific to Raldh2 was packaged and constructed by RNA interference (RNAi) method.The P19 stable cell line carried Raldh2 miRNA expression was selected by adding blasticidin and induced to differentiate towards cardiomyocyte-like cells.The mRNA levels of myocardium development-related markers were determined by qPCR at different stages during the differentiation process.Results The miRNA expression plasmid specific to Raldh2 could effectively suppress Raldh2 expression,and the MiRaldh2 group,a P19 stable cell line was established successfully in which the knockdown efficiency on Raldh2 was 91％ (t =25.52,P＜0.000 1,95％ CI:0.81-1.01).When compared with P19 group,the mRNA levels of cardiac transcription factors were generally decreased in the MiRaldh2 group during the whole differentiation process.In detail,on the 7th day,the relatively low expression rates of these cardiac markers including Gata4,Tef-1,N-myc,α-mhc and Ctnt was0.16±0.01 (t=17.29,P＜0.000 1),0.51 ±0.02 (t=3.564,P=0.023 5),0.23 ±0.01 (t=13.17,P =0.000 2),0.20 ± 0.02 (t=17.76,P＜0.000 1) and 0.59 ± 0.06 (t =3.642,P =0.021 9) in MiRaldh2 group when compared with the P19 group.Conversely,the mRNA levels of Nkx2.5 and Hand2 were dramatically increased in MiRaldh2 group on day 2 to 7 and the expression rates on the 7th day was 2.25 ± 0.35 (t =3.526,P =0.024 3) compared with the P19 group while Hand2 was 3.58 ± 0.20 (t =9.214,P =0.011 6).Conclusions Knockdown of Raldh2 inhibits the P19 cells differentiated into cardiomyocyte-like cells,which suggests that Raldh2 may play a potential role in early development of heart.The low expression of Raldh2 might be an explanation of the cardiac malformations associated with retinoic acid deficiency.
RESUMEN
El ácido retinoico tópico es eficaz para el tratamiento del fotoenvejecimiento. Sin embargo la irritación cutánea secundaria a su uso es un factor limitante del tratamiento. El retinaldehído es un precursor inmediato del ácido retinoico que posee actividad biológica en la piel, con menos efectos secundarios. Objetivo: comparar la eficacia y tolerancia del retinaldehido y el ácido retinoico tópicos en el tratamiento del fotoenvejecimiento, mediante perfil profilométrico y análisis clínico - fotográfico y determinar los efectos secundarios de estos medicamentos. Métodos: se incluyeron 126 mujeres colombianas (35 a 60 años), quienes no habían recibido tratamientos previos, no estaban embarazadas, ni lactando. En total 119 pacientes completaron las 24 semanas de seguimiento: a 61 pacientes se les aplicó retinaldehído y a 58, ácido retinoico. Se realizó un seguimiento clínico (que evaluó mejoría y tolerancia), en las semanas 4, 8, 16 y 20, y además se realizó profilometría del área de la pata de gallina y seguimiento fotográfico al ingreso y en la semana 24.
Topical retinoic acid has been effectively used to treat photo aging; nevertheless, cutaneous irritation as a side effect is a limiting factor for treatment. Retinaldehyde is an immediate precursor of retinoic acid that has biologic activity in the skin, with few side effects. The objective of this investigation was to compare efficacy and tolerability of topical retinoic acid and retinaldehyde in the treatment of photo aging, by means of profilometry and clinical-photographic analysis and to determine side effects from both medications. Methods: were included 160 colombian women (aged 35 to 60 years), who hadn't had previous treatments and weren't pregnant or breast feeding. A total of 119 patients completed 24 weeks of treatment. Of these, 61 used retinaldehyde and 58 retinoic acid. Clinical evaluation was carried out on weeks 4, 8, 16 and 20, and profilometry of the crow's feet area was done at the beginning and at week 24.