Limits...
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.


Size of ARSB- mice, and measurements of arylsulfatase B activity, chondroitin 4-sulfate, and sulfotransferase activity.(A) Images of the ARSB control and  mice show a significant size disparity. (B) At twelve weeks, ARSB- mice were significantly smaller than control mice (total n = 17). (C) At twelve weeks, the ARSB- mice weighed significantly less than the control mice. (D) ARSB activity was significantly less in the ARSB- mouse hepatic tissue than in the age-matched normal C57BL/6J controls. Values were similar for male and female mice. (E) Consistent with the known reduction in ARSB activity in the hepatic tissue of ARSB- mice, the total sulfated glycosaminoglycan (GAG) content in the hepatic tissue of the ARSB- mice was significantly greater than in the controls (n = 20). (F) The chondroitin 4-sulfate (C4S) content was also significantly greater in the ARSB- mice. The increase in total sulfated GAG was largely attributable to the increase in C4S. (G) In primary hepatocytes from the ARSB  and C57BL/6J control mice, the ARSB activity in the hepatocytes from the ARSB- mice was significantly less than from the controls (pn = 6). (H) Consistent with the decline in ARSB activity, the total sulfated GAG was markedly increased in the primary hepatocytes from the ARSB- mice, compared to the normal control (n = 6). (I) Similarly, the C4S in the primary hepatocytes from the ARSB- mice was significantly greater than in the controls. (J) The mitochondria isolated from the hepatic tissue of the control mice had lower ARSB activity than the primary hepatocytes from the control hepatic tissue (27.6 ± 2.8 nmol/mg protein/h vs. 117.8 ± 6.6 nmol/mg protein/h). In the ARSB  mice, the mitochondrial ARSB activity was virtually absent. (K). The chondroitin 4-sulfate level in the hepatic mitochondria was higher in the ARSB- mice than in the control mice, but was markedly less than in the primary hepatocytes. (L) Sulfotransferase activity was absent in the mitochondrial preparation from both control and ARSB- mouse hepatic tissue (n = 3). [ARSB = arylsulfatase B (N-acetylgalactosamine 4-sulfatase); C4S = chondroitin 4-sulfate; c = control; F = female; M = male;  = ARSB-; ST = sulfotransferase; WT = weight]
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC5015117&req=5

f1: Size of ARSB- mice, and measurements of arylsulfatase B activity, chondroitin 4-sulfate, and sulfotransferase activity.(A) Images of the ARSB control and mice show a significant size disparity. (B) At twelve weeks, ARSB- mice were significantly smaller than control mice (total n = 17). (C) At twelve weeks, the ARSB- mice weighed significantly less than the control mice. (D) ARSB activity was significantly less in the ARSB- mouse hepatic tissue than in the age-matched normal C57BL/6J controls. Values were similar for male and female mice. (E) Consistent with the known reduction in ARSB activity in the hepatic tissue of ARSB- mice, the total sulfated glycosaminoglycan (GAG) content in the hepatic tissue of the ARSB- mice was significantly greater than in the controls (n = 20). (F) The chondroitin 4-sulfate (C4S) content was also significantly greater in the ARSB- mice. The increase in total sulfated GAG was largely attributable to the increase in C4S. (G) In primary hepatocytes from the ARSB and C57BL/6J control mice, the ARSB activity in the hepatocytes from the ARSB- mice was significantly less than from the controls (pn = 6). (H) Consistent with the decline in ARSB activity, the total sulfated GAG was markedly increased in the primary hepatocytes from the ARSB- mice, compared to the normal control (n = 6). (I) Similarly, the C4S in the primary hepatocytes from the ARSB- mice was significantly greater than in the controls. (J) The mitochondria isolated from the hepatic tissue of the control mice had lower ARSB activity than the primary hepatocytes from the control hepatic tissue (27.6 ± 2.8 nmol/mg protein/h vs. 117.8 ± 6.6 nmol/mg protein/h). In the ARSB mice, the mitochondrial ARSB activity was virtually absent. (K). The chondroitin 4-sulfate level in the hepatic mitochondria was higher in the ARSB- mice than in the control mice, but was markedly less than in the primary hepatocytes. (L) Sulfotransferase activity was absent in the mitochondrial preparation from both control and ARSB- mouse hepatic tissue (n = 3). [ARSB = arylsulfatase B (N-acetylgalactosamine 4-sulfatase); C4S = chondroitin 4-sulfate; c = control; F = female; M = male;  = ARSB-; ST = sulfotransferase; WT = weight]

Mentions: Like patients with MPS VI, ARSB- mice are small, with lower body weight and length than age- and gender-matched C57BL/6J controls (total n = 17) (Fig. 1A). Body length (Fig. 1B) and body weight (Fig. 1C) of ARSB- male and female mice were significantly less than in matched, control mice at ~12 weeks.


Restriction of Aerobic Metabolism by Acquired or Innate Arylsulfatase B Deficiency: A New Approach to the Warburg Effect
Size of ARSB- mice, and measurements of arylsulfatase B activity, chondroitin 4-sulfate, and sulfotransferase activity.(A) Images of the ARSB control and  mice show a significant size disparity. (B) At twelve weeks, ARSB- mice were significantly smaller than control mice (total n = 17). (C) At twelve weeks, the ARSB- mice weighed significantly less than the control mice. (D) ARSB activity was significantly less in the ARSB- mouse hepatic tissue than in the age-matched normal C57BL/6J controls. Values were similar for male and female mice. (E) Consistent with the known reduction in ARSB activity in the hepatic tissue of ARSB- mice, the total sulfated glycosaminoglycan (GAG) content in the hepatic tissue of the ARSB- mice was significantly greater than in the controls (n = 20). (F) The chondroitin 4-sulfate (C4S) content was also significantly greater in the ARSB- mice. The increase in total sulfated GAG was largely attributable to the increase in C4S. (G) In primary hepatocytes from the ARSB  and C57BL/6J control mice, the ARSB activity in the hepatocytes from the ARSB- mice was significantly less than from the controls (pn = 6). (H) Consistent with the decline in ARSB activity, the total sulfated GAG was markedly increased in the primary hepatocytes from the ARSB- mice, compared to the normal control (n = 6). (I) Similarly, the C4S in the primary hepatocytes from the ARSB- mice was significantly greater than in the controls. (J) The mitochondria isolated from the hepatic tissue of the control mice had lower ARSB activity than the primary hepatocytes from the control hepatic tissue (27.6 ± 2.8 nmol/mg protein/h vs. 117.8 ± 6.6 nmol/mg protein/h). In the ARSB  mice, the mitochondrial ARSB activity was virtually absent. (K). The chondroitin 4-sulfate level in the hepatic mitochondria was higher in the ARSB- mice than in the control mice, but was markedly less than in the primary hepatocytes. (L) Sulfotransferase activity was absent in the mitochondrial preparation from both control and ARSB- mouse hepatic tissue (n = 3). [ARSB = arylsulfatase B (N-acetylgalactosamine 4-sulfatase); C4S = chondroitin 4-sulfate; c = control; F = female; M = male;  = ARSB-; ST = sulfotransferase; WT = weight]
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5015117&req=5

f1: Size of ARSB- mice, and measurements of arylsulfatase B activity, chondroitin 4-sulfate, and sulfotransferase activity.(A) Images of the ARSB control and mice show a significant size disparity. (B) At twelve weeks, ARSB- mice were significantly smaller than control mice (total n = 17). (C) At twelve weeks, the ARSB- mice weighed significantly less than the control mice. (D) ARSB activity was significantly less in the ARSB- mouse hepatic tissue than in the age-matched normal C57BL/6J controls. Values were similar for male and female mice. (E) Consistent with the known reduction in ARSB activity in the hepatic tissue of ARSB- mice, the total sulfated glycosaminoglycan (GAG) content in the hepatic tissue of the ARSB- mice was significantly greater than in the controls (n = 20). (F) The chondroitin 4-sulfate (C4S) content was also significantly greater in the ARSB- mice. The increase in total sulfated GAG was largely attributable to the increase in C4S. (G) In primary hepatocytes from the ARSB and C57BL/6J control mice, the ARSB activity in the hepatocytes from the ARSB- mice was significantly less than from the controls (pn = 6). (H) Consistent with the decline in ARSB activity, the total sulfated GAG was markedly increased in the primary hepatocytes from the ARSB- mice, compared to the normal control (n = 6). (I) Similarly, the C4S in the primary hepatocytes from the ARSB- mice was significantly greater than in the controls. (J) The mitochondria isolated from the hepatic tissue of the control mice had lower ARSB activity than the primary hepatocytes from the control hepatic tissue (27.6 ± 2.8 nmol/mg protein/h vs. 117.8 ± 6.6 nmol/mg protein/h). In the ARSB mice, the mitochondrial ARSB activity was virtually absent. (K). The chondroitin 4-sulfate level in the hepatic mitochondria was higher in the ARSB- mice than in the control mice, but was markedly less than in the primary hepatocytes. (L) Sulfotransferase activity was absent in the mitochondrial preparation from both control and ARSB- mouse hepatic tissue (n = 3). [ARSB = arylsulfatase B (N-acetylgalactosamine 4-sulfatase); C4S = chondroitin 4-sulfate; c = control; F = female; M = male;  = ARSB-; ST = sulfotransferase; WT = weight]
Mentions: Like patients with MPS VI, ARSB- mice are small, with lower body weight and length than age- and gender-matched C57BL/6J controls (total n = 17) (Fig. 1A). Body length (Fig. 1B) and body weight (Fig. 1C) of ARSB- male and female mice were significantly less than in matched, control mice at ~12 weeks.

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.