Abstract
Liver is the central metabolic hub that coordinates carbohydrate and lipid metabolism. The bioactive derivative of vitamin A, retinoic acid (RA), was shown to regulate major metabolic genes including phosphoenolpyruvate carboxykinase, fatty acid synthase, carnitine palmitoyltransferase 1, and glucokinase among others. Expression levels of these genes undergo profound changes during adaptation to fasting or in metabolic diseases such as type 1 diabetes (T1D). However, it is unknown whether the levels of hepatic RA change during metabolic remodeling. This study investigated the dynamics of hepatic retinoid metabolism and signaling in the fed state, in fasting, and in T1D. Our results show that fed-to-fasted transition is associated with significant decrease in hepatic retinol dehydrogenase (RDH) activity, the rate-limiting step in RA biosynthesis, and downregulation of RA signaling. The decrease in RDH activity correlates with the decreased abundance and altered subcellular distribution of RDH10 while Rdh10 transcript levels remain unchanged. In contrast to fasting, untreated T1D is associated with upregulation of RA signaling and an increase in hepatic RDH activity, which correlates with the increased abundance of RDH10 in microsomal membranes. The dynamic changes in RDH10 protein levels in the absence of changes in its transcript levels imply the existence of posttranscriptional regulation of RDH10 protein. Together, these data suggest that the downregulation of hepatic RA biosynthesis, in part via the decrease in RDH10, is an integral component of adaptation to fasting. In contrast, the upregulation of hepatic RA biosynthesis and signaling in T1D might contribute to metabolic inflexibility associated with this disease.
Highlights
Numerous studies have demonstrated that the bioactive derivative of vitamin A, retinoic acid (RA), is essential for proper embryonic development [1,2,3], robust immune responses [4, 5], male fertility [6, 7], epigenetic regulation [8,9,10], and maintenance of circadian rhythms [11,12,13]
The dramatic decrease in expression of Cyp26a1 along with downregulation in expression of Lrat, which is an RA-sensitive gene [34], and decreases in Rbp1 and Rdh11 expression suggest that the extensive metabolic remodeling that occurs during the fed-to-fasted transition might include adaptive changes in retinoid metabolism and signaling
In conjunction with other results showing that fasting is associated with changes in RA-regulated transcriptome (Fig. 1B); the decreased abundance of RDH10 and DHRS3 proteins (Fig. 2); as well as the decrease in the NAD+dependent retinol dehydrogenase activity in MT, MS, and lipid droplets (LD) fractions isolated from the livers of fasted mice (Fig. 3, A and B), the lower RA levels in 16 h-fasted livers suggest that metabolic stress and remodeling associated with fasting affect RA biosynthesis and signaling
Summary
To characterize the dynamics of RA signaling during the fed-to-fasted transition, we chose two time points: 16 h and 24 h after beginning of fasting. The results of western blot analysis (Fig. 2) suggested that fasting causes a substantial decrease in the overall hepatic content of RDH10 protein as well as changes in its subcellular distribution To determine whether these changes affected the overall NAD+-dependent retinol dehydrogenase activity, we assayed the oxidation of retinol to retinaldehyde by MT, MS, and LDs isolated from the livers of fed and fasted mice. In conjunction with other results showing that fasting is associated with changes in RA-regulated transcriptome (Fig. 1B); the decreased abundance of RDH10 and DHRS3 proteins (Fig. 2); as well as the decrease in the NAD+dependent retinol dehydrogenase activity in MT, MS, and LD fractions isolated from the livers of fasted mice (Fig. 3, A and B), the lower RA levels in 16 h-fasted livers suggest that metabolic stress and remodeling associated with fasting affect RA biosynthesis and signaling.
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