Limits...
Renal response to short- and long-term exercise in very-long-chain acyl-CoA dehydrogenase-deficient (VLCAD − / − ) mice

View Article: PubMed Central

ABSTRACT

Background: Deficiency of very long-chain acyl-CoA dehydrogenase (VLCAD) is the most common disorder of mitochondrial β-oxidation of long-chain fatty acids. In order to maintain glucose homeostasis, the kidney and liver as the main gluconeogenic organs play an important role under conditions of impaired fatty acid oxidation. However, little is known about how a defective fatty acid oxidation machinery affects renal metabolism and function as well as renal energy supply especially during catabolic situations.

Methods: In this study, we analyzed VLCAD−/− mice under different metabolic conditions such as after moderate (1 h) and intensive long-term (1 h twice per day over 2 weeks) physical exercise and after 24 h of fasting. We measured the oxidation rate of palmitoyl-CoA (C16-CoA) as well as the expression of genes involved in lipogenesis and renal failure. Oxidative stress was assessed by the function of antioxidant enzymes. Moreover, we quantified the content of glycogen and long-chain acylcarnitines in the kidney.

Results: We observed a significant depletion in renal glycogen with a concomitant reduction in long-chain acylcarnitines, suggesting a substrate switch for energy production and an optimal compensation of impaired fatty acid oxidation in the kidney. In fact, the mutants did not show any signs of oxidative stress or renal failure under catabolic conditions.

Conclusions: Our data demonstrate that despite Acadvl ablation, the kidney of VLCAD−/− mice fully compensates for impaired fatty acid oxidation by enhanced glycogen utilization and preserves renal energy metabolism and function.

No MeSH data available.


Renal lipogenesis is not affected under different stress conditions. (A)SREBP-1c, stearoyl-regulatory element binding protein 1c. (B)FASN, fatty acid synthetase. (C)ACC1α, acetyl-CoA carboxylase α. White and black bars represent WT and VLCAD−/− mice, respectively. Values are represented as mean ± SEM (n = 5 to 6). Asterisk indicates significant differences between WT and VLCAD−/− mice within an experimental set. Number sign indicates significant differences between WT or VLCAD−/− mice under different stress conditions as compared to resting mice. Asterisk and number sign denote that values were considered significant if p < 0.05 (two-way ANOVA with Bonferroni correction and Student's t test).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4530567&req=5

Fig2: Renal lipogenesis is not affected under different stress conditions. (A)SREBP-1c, stearoyl-regulatory element binding protein 1c. (B)FASN, fatty acid synthetase. (C)ACC1α, acetyl-CoA carboxylase α. White and black bars represent WT and VLCAD−/− mice, respectively. Values are represented as mean ± SEM (n = 5 to 6). Asterisk indicates significant differences between WT and VLCAD−/− mice within an experimental set. Number sign indicates significant differences between WT or VLCAD−/− mice under different stress conditions as compared to resting mice. Asterisk and number sign denote that values were considered significant if p < 0.05 (two-way ANOVA with Bonferroni correction and Student's t test).

Mentions: Because catabolism stimulates lipolysis resulting in marked lipid accumulation in different organs of VLCAD−/− mice [11], we measured the renal lipogenesis in all groups. We therefore tested the expression at mRNA level of genes involved in this pathway, such as the transcription factor SREBP-1c, which regulates lipid homeostasis, fatty acid biosynthesis, and glucose metabolism [25], as well as of its target genes ACC1α and FASN, responsible for de novo biosynthesis and elongation of fatty acids as they directly correlate with the triglyceride accumulation in the kidney [26]. As shown in Figure 2A,B,C, in contrast to results previously obtained from the liver [11,12], the expression of these genes was strongly downregulated in all groups independently of the applied stress.Figure 2


Renal response to short- and long-term exercise in very-long-chain acyl-CoA dehydrogenase-deficient (VLCAD − / − ) mice
Renal lipogenesis is not affected under different stress conditions. (A)SREBP-1c, stearoyl-regulatory element binding protein 1c. (B)FASN, fatty acid synthetase. (C)ACC1α, acetyl-CoA carboxylase α. White and black bars represent WT and VLCAD−/− mice, respectively. Values are represented as mean ± SEM (n = 5 to 6). Asterisk indicates significant differences between WT and VLCAD−/− mice within an experimental set. Number sign indicates significant differences between WT or VLCAD−/− mice under different stress conditions as compared to resting mice. Asterisk and number sign denote that values were considered significant if p < 0.05 (two-way ANOVA with Bonferroni correction and Student's t test).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4530567&req=5

Fig2: Renal lipogenesis is not affected under different stress conditions. (A)SREBP-1c, stearoyl-regulatory element binding protein 1c. (B)FASN, fatty acid synthetase. (C)ACC1α, acetyl-CoA carboxylase α. White and black bars represent WT and VLCAD−/− mice, respectively. Values are represented as mean ± SEM (n = 5 to 6). Asterisk indicates significant differences between WT and VLCAD−/− mice within an experimental set. Number sign indicates significant differences between WT or VLCAD−/− mice under different stress conditions as compared to resting mice. Asterisk and number sign denote that values were considered significant if p < 0.05 (two-way ANOVA with Bonferroni correction and Student's t test).
Mentions: Because catabolism stimulates lipolysis resulting in marked lipid accumulation in different organs of VLCAD−/− mice [11], we measured the renal lipogenesis in all groups. We therefore tested the expression at mRNA level of genes involved in this pathway, such as the transcription factor SREBP-1c, which regulates lipid homeostasis, fatty acid biosynthesis, and glucose metabolism [25], as well as of its target genes ACC1α and FASN, responsible for de novo biosynthesis and elongation of fatty acids as they directly correlate with the triglyceride accumulation in the kidney [26]. As shown in Figure 2A,B,C, in contrast to results previously obtained from the liver [11,12], the expression of these genes was strongly downregulated in all groups independently of the applied stress.Figure 2

View Article: PubMed Central

ABSTRACT

Background: Deficiency of very long-chain acyl-CoA dehydrogenase (VLCAD) is the most common disorder of mitochondrial &beta;-oxidation of long-chain fatty acids. In order to maintain glucose homeostasis, the kidney and liver as the main gluconeogenic organs play an important role under conditions of impaired fatty acid oxidation. However, little is known about how a defective fatty acid oxidation machinery affects renal metabolism and function as well as renal energy supply especially during catabolic situations.

Methods: In this study, we analyzed VLCAD&minus;/&minus; mice under different metabolic conditions such as after moderate (1&nbsp;h) and intensive long-term (1&nbsp;h twice per day over 2&nbsp;weeks) physical exercise and after 24&nbsp;h of fasting. We measured the oxidation rate of palmitoyl-CoA (C16-CoA) as well as the expression of genes involved in lipogenesis and renal failure. Oxidative stress was assessed by the function of antioxidant enzymes. Moreover, we quantified the content of glycogen and long-chain acylcarnitines in the kidney.

Results: We observed a significant depletion in renal glycogen with a concomitant reduction in long-chain acylcarnitines, suggesting a substrate switch for energy production and an optimal compensation of impaired fatty acid oxidation in the kidney. In fact, the mutants did not show any signs of oxidative stress or renal failure under catabolic conditions.

Conclusions: Our data demonstrate that despite Acadvl ablation, the kidney of VLCAD&minus;/&minus; mice fully compensates for impaired fatty acid oxidation by enhanced glycogen utilization and preserves renal energy metabolism and function.

No MeSH data available.