Glycerol kinase deficiency in adipose tissue

A 50-year-old, alcoholic male presents with a swollen face, distended abdomen, and an enlarged fatty liver. Fatty acids react with glycerol-3-P to form triglycerides, which accumulate to cause fatty liver. The liver has glycerol kinase, while adipose tissue lacks glycerol kinase. As a result, in adipose tissue, which of the following occurs?

A) Glucose cannot be converted to DHAP (dihydroxyacetone phosphate)

B) Glycerol cannot be converted to Glycerol-3-P

C) DHAP cannot be converted to Glycerol-3-P

D) Diacylglycerol cannot be converted to Triacylglycerol

E) Triacylglycerols cannot be stored.

The correct answer is- B) – Glycerol cannot be converted to Glycerol-3-P.

Glycerol kinase catalyzes the phosphorylation of glycerol to glycerol-3-p.

Glycerol released through adipolysis (breakdown of triglycerides) cannot be reutilized, as it has to be in the phosphorylated form, and glycerol kinase deficiency in adipose tissue makes glycerol a waste product (figure).

Therefore Glycerol is transported to liver, where upon conversion to dihydroxy acetone phosphate, (figure), it is either converted to glucose (through pathway of gluconeogenesis), or is completely oxidized through glycolytic pathway. The fate of glycerol is decided by the cellular requirements.

1)  In the fasting state- Glycerol released from lipolysis of adipose tissue triacylglycerol is used solely as a substrate for gluconeogenesis in the liver and kidneys. The conversion of glycerol to glucose requires phosphorylation to glycerol-3-phosphate by glycerol kinase and dehydrogenation to Dihydroxyacetone phosphate (DHAP) by glyceraldehyde-3-phosphate dehydrogenase (G3PDH) (Figure). The G3PDH reaction is the same as that used in the transport of cytosolic reducing equivalents into the mitochondrion for use in oxidative phosphorylation. This transport pathway is called the glycerol-phosphate shuttle.

Fate of glycerol

Figure-Glucose-Glycerol cycle. Glycerol released from adipocyte is used in the liver either for energy production or is utilized as a substrate for gluconeogenesis. Glycerol is initially converted to glycerol-3-P, in a reaction catalyzed by glycerol kinase. Subsequently glycerol-3-P is converted to Dihydroxy acetone-P (DHAP) by glycerol-3-p dehydrogenase. It is a reversible reaction. DHAP can then enter the pathway of glucose production. Glucose produced is transported back to adipocyte to complete the cycle. The entry of glucose in the adipocyte is by GLUT4 receptors that are regulated by Insulin.

2) In the well fed state- Glycerol upon conversion to DHAP in liver (as described above), is oxidized completely through the pathway of glycolysis. Glycolytic pathway is involved both for the utilization and production of glycerol-3-P.

It is noteworthy that glycerol-3-P in adipose tissue is obtained through glycolytic pathway (figure), and not by direct phosphorylation of glycerol (glycerol kinase is absent in adipose tissue).  In fact adipocytes require a basal level of glycolysis in order to provide them with DHAP as an intermediate in the synthesis of triacylglycerols.

As regards other options

A) Glucose cannot be converted to DHAP (dihydroxy acetone phosphate) – This in incorrect, Glucose can be converted to DHAP through glycolytic pathway (figure).

C) DHAP cannot be converted to Glycerol-3-P- This is also incorrect, DHAP is converted to Glycerol-3-P, in a reaction catalyzed by Glycerol-3-P dehydrogenase.

D) Diacylglycerol cannot be converted to Triacylglycerol- Diacyl glycerol can be converted to triacylglycerol. This is also not a correct option.

E) Triacylglycerols cannot be stored- Incorrect again, Triacylglycerols can be stored in an unlimited amount in the adipose cells.

Thus the most appropriate option is B) – Glycerol cannot be converted to Glycerol-3-P due to deficiency of glycerol kinase.








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