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Restriction of Aerobic Metabolism by Acquired or Innate Arylsulfatase B Deficiency: A New Approach to the Warburg Effect

View Article: PubMed Central - PubMed

ABSTRACT

Aerobic respiration is required for optimal efficiency of metabolism in mammalian cells. Under circumstances when oxygen utilization is impaired, cells survive by anerobic metabolism. The malignant cell has cultivated the use of anerobic metabolism in an aerobic environment, the Warburg effect, but the explanation for this preference is not clear. This paper presents evidence that deficiency of the enzyme arylsulfatase B (ARSB; N-acetylgalactosamine 4-sulfatase), either innate or acquired, helps to explain the Warburg phenomenon. ARSB is the enzyme that removes 4-sulfate groups from the non-reducing end of chondroitin 4-sulfate and dermatan sulfate. Previous reports indicated reduced ARSB activity in malignancy and replication of the effects of hypoxia by decline in ARSB. Hypoxia reduced ARSB activity, since molecular oxygen is needed for post-translational modification of ARSB. In this report, studies were performed in human HepG2 cells and in hepatocytes from ARSB-deficient and normal C57BL/6J control mice. Decline of ARSB, in the presence of oxygen, profoundly reduced the oxygen consumption rate and increased the extracellular acidification rate, indicating preference for aerobic glycolysis. Specific study findings indicate that decline in ARSB activity enhanced aerobic glycolysis and impaired normal redox processes, consistent with a critical role of ARSB and sulfate reduction in mammalian metabolism.

No MeSH data available.


Related in: MedlinePlus

NAD+/NADH and NADP+/NADPH ratios, NADH and NADPH oxidase activity, and GSH/GSSG ratio and thiol content.(A) The ratio of NAD+ to NADH is significantly lower in the ARSB- mouse hepatic tissue, mainly due to increase in NADH, which increased by ~66 ng/mg protein in the ARSB- mouse hepatic tissue (n = 20). (B) In the ARSB- mouse hepatic tissue, the ratio of NADP+ to NADPH was also less, largely attributable to an increase in NADPH of ~9.5 ng/mg protein (n = 20). (C) Consistent with the increase in NADH, the NADH oxidase was significantly less in the ARSB- mice (n = 12). (D) Consistent with the observed increase in NADPH, the NADPH oxidase activity was less in the ARSB- hepatic tissue (n = 20). (E) In the ARSB-silenced HepG2 cells, the ratio of NAD+ to NADH was also significantly less, due predominantly to increase of ~80 ng/mg protein in NADH (n = 3). (F) In the ARSB-silenced HepG2 cells, the ratio of NADP+ to NADPH was significantly less, due to increase of ~8 ng/mg protein in NADPH (n = 3). (G) In contrast to the increases in the reduced forms NADH and NADPH when ARSB was lower in the ARSB- mouse hepatic tissue, the ratio of glutathione (GSSG) to reduced glutathione (GSH) was increased, due to decline in reduced glutathione (n = 12). (H) Similarly, the level of thiols was significantly reduced in the ARSB- hepatic tissue, demonstrating an overall decline in reduced sulfur products when ARSB activity was less (n = 12). [ARSB = arylsulfatase B; CF = control female; CM = control male; GSH = glutathione; GSSG = glutathione disulfide].
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f6: NAD+/NADH and NADP+/NADPH ratios, NADH and NADPH oxidase activity, and GSH/GSSG ratio and thiol content.(A) The ratio of NAD+ to NADH is significantly lower in the ARSB- mouse hepatic tissue, mainly due to increase in NADH, which increased by ~66 ng/mg protein in the ARSB- mouse hepatic tissue (n = 20). (B) In the ARSB- mouse hepatic tissue, the ratio of NADP+ to NADPH was also less, largely attributable to an increase in NADPH of ~9.5 ng/mg protein (n = 20). (C) Consistent with the increase in NADH, the NADH oxidase was significantly less in the ARSB- mice (n = 12). (D) Consistent with the observed increase in NADPH, the NADPH oxidase activity was less in the ARSB- hepatic tissue (n = 20). (E) In the ARSB-silenced HepG2 cells, the ratio of NAD+ to NADH was also significantly less, due predominantly to increase of ~80 ng/mg protein in NADH (n = 3). (F) In the ARSB-silenced HepG2 cells, the ratio of NADP+ to NADPH was significantly less, due to increase of ~8 ng/mg protein in NADPH (n = 3). (G) In contrast to the increases in the reduced forms NADH and NADPH when ARSB was lower in the ARSB- mouse hepatic tissue, the ratio of glutathione (GSSG) to reduced glutathione (GSH) was increased, due to decline in reduced glutathione (n = 12). (H) Similarly, the level of thiols was significantly reduced in the ARSB- hepatic tissue, demonstrating an overall decline in reduced sulfur products when ARSB activity was less (n = 12). [ARSB = arylsulfatase B; CF = control female; CM = control male; GSH = glutathione; GSSG = glutathione disulfide].

Mentions: In the ARSB-deficient mouse hepatic tissue, the ratios of NAD+ to NADH (Fig. 6A) and NADP+ to NADPH (Fig. 6B) were markedly less, compared to levels in the normal controls. The NAD+/NADH ratios of control mice were 2.93 ± 0.26 (n = 10). These ratios were significantly lower in the ARSB- mice (1.80 ± 0.21, p < 0.0001; n = 10). The declines in the ratios were due predominantly to increases in the reduced forms of NADH and NADPH. In the ARSB- female mouse hepatic tissue, NADH increased to 201.8 ± 12.1 ng/mg protein from 135.8 ± 9.4 ng/mg protein (p < 0.0001), and NADPH increased to 36.5 ± 1.7 ng/mg protein from 26.9 ± 1.2 ng/mg protein in the female mice and to 35.7 ± 1.0 ng/mg protein from 26.9 ± 3.9 ng/mg protein in the male mice (p < 0.0001; p = 0.001). The activities of NADH oxidase (Fig. 6C) and of NADPH oxidase (Fig. 6D) were significantly less in the ARSB- hepatic tissue (p < 0.0001) than in the control tissue.


Restriction of Aerobic Metabolism by Acquired or Innate Arylsulfatase B Deficiency: A New Approach to the Warburg Effect
NAD+/NADH and NADP+/NADPH ratios, NADH and NADPH oxidase activity, and GSH/GSSG ratio and thiol content.(A) The ratio of NAD+ to NADH is significantly lower in the ARSB- mouse hepatic tissue, mainly due to increase in NADH, which increased by ~66 ng/mg protein in the ARSB- mouse hepatic tissue (n = 20). (B) In the ARSB- mouse hepatic tissue, the ratio of NADP+ to NADPH was also less, largely attributable to an increase in NADPH of ~9.5 ng/mg protein (n = 20). (C) Consistent with the increase in NADH, the NADH oxidase was significantly less in the ARSB- mice (n = 12). (D) Consistent with the observed increase in NADPH, the NADPH oxidase activity was less in the ARSB- hepatic tissue (n = 20). (E) In the ARSB-silenced HepG2 cells, the ratio of NAD+ to NADH was also significantly less, due predominantly to increase of ~80 ng/mg protein in NADH (n = 3). (F) In the ARSB-silenced HepG2 cells, the ratio of NADP+ to NADPH was significantly less, due to increase of ~8 ng/mg protein in NADPH (n = 3). (G) In contrast to the increases in the reduced forms NADH and NADPH when ARSB was lower in the ARSB- mouse hepatic tissue, the ratio of glutathione (GSSG) to reduced glutathione (GSH) was increased, due to decline in reduced glutathione (n = 12). (H) Similarly, the level of thiols was significantly reduced in the ARSB- hepatic tissue, demonstrating an overall decline in reduced sulfur products when ARSB activity was less (n = 12). [ARSB = arylsulfatase B; CF = control female; CM = control male; GSH = glutathione; GSSG = glutathione disulfide].
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f6: NAD+/NADH and NADP+/NADPH ratios, NADH and NADPH oxidase activity, and GSH/GSSG ratio and thiol content.(A) The ratio of NAD+ to NADH is significantly lower in the ARSB- mouse hepatic tissue, mainly due to increase in NADH, which increased by ~66 ng/mg protein in the ARSB- mouse hepatic tissue (n = 20). (B) In the ARSB- mouse hepatic tissue, the ratio of NADP+ to NADPH was also less, largely attributable to an increase in NADPH of ~9.5 ng/mg protein (n = 20). (C) Consistent with the increase in NADH, the NADH oxidase was significantly less in the ARSB- mice (n = 12). (D) Consistent with the observed increase in NADPH, the NADPH oxidase activity was less in the ARSB- hepatic tissue (n = 20). (E) In the ARSB-silenced HepG2 cells, the ratio of NAD+ to NADH was also significantly less, due predominantly to increase of ~80 ng/mg protein in NADH (n = 3). (F) In the ARSB-silenced HepG2 cells, the ratio of NADP+ to NADPH was significantly less, due to increase of ~8 ng/mg protein in NADPH (n = 3). (G) In contrast to the increases in the reduced forms NADH and NADPH when ARSB was lower in the ARSB- mouse hepatic tissue, the ratio of glutathione (GSSG) to reduced glutathione (GSH) was increased, due to decline in reduced glutathione (n = 12). (H) Similarly, the level of thiols was significantly reduced in the ARSB- hepatic tissue, demonstrating an overall decline in reduced sulfur products when ARSB activity was less (n = 12). [ARSB = arylsulfatase B; CF = control female; CM = control male; GSH = glutathione; GSSG = glutathione disulfide].
Mentions: In the ARSB-deficient mouse hepatic tissue, the ratios of NAD+ to NADH (Fig. 6A) and NADP+ to NADPH (Fig. 6B) were markedly less, compared to levels in the normal controls. The NAD+/NADH ratios of control mice were 2.93 ± 0.26 (n = 10). These ratios were significantly lower in the ARSB- mice (1.80 ± 0.21, p < 0.0001; n = 10). The declines in the ratios were due predominantly to increases in the reduced forms of NADH and NADPH. In the ARSB- female mouse hepatic tissue, NADH increased to 201.8 ± 12.1 ng/mg protein from 135.8 ± 9.4 ng/mg protein (p < 0.0001), and NADPH increased to 36.5 ± 1.7 ng/mg protein from 26.9 ± 1.2 ng/mg protein in the female mice and to 35.7 ± 1.0 ng/mg protein from 26.9 ± 3.9 ng/mg protein in the male mice (p < 0.0001; p = 0.001). The activities of NADH oxidase (Fig. 6C) and of NADPH oxidase (Fig. 6D) were significantly less in the ARSB- hepatic tissue (p < 0.0001) than in the control tissue.

View Article: PubMed Central - PubMed

ABSTRACT

Aerobic respiration is required for optimal efficiency of metabolism in mammalian cells. Under circumstances when oxygen utilization is impaired, cells survive by anerobic metabolism. The malignant cell has cultivated the use of anerobic metabolism in an aerobic environment, the Warburg effect, but the explanation for this preference is not clear. This paper presents evidence that deficiency of the enzyme arylsulfatase B (ARSB; N-acetylgalactosamine 4-sulfatase), either innate or acquired, helps to explain the Warburg phenomenon. ARSB is the enzyme that removes 4-sulfate groups from the non-reducing end of chondroitin 4-sulfate and dermatan sulfate. Previous reports indicated reduced ARSB activity in malignancy and replication of the effects of hypoxia by decline in ARSB. Hypoxia reduced ARSB activity, since molecular oxygen is needed for post-translational modification of ARSB. In this report, studies were performed in human HepG2 cells and in hepatocytes from ARSB-deficient and normal C57BL/6J control mice. Decline of ARSB, in the presence of oxygen, profoundly reduced the oxygen consumption rate and increased the extracellular acidification rate, indicating preference for aerobic glycolysis. Specific study findings indicate that decline in ARSB activity enhanced aerobic glycolysis and impaired normal redox processes, consistent with a critical role of ARSB and sulfate reduction in mammalian metabolism.

No MeSH data available.


Related in: MedlinePlus