glycerol kinase

**Reaction:** Glycerol + ATP → glycerol-3-phosphate + ADP (cytosol). Glycerol-3-phosphate is then oxidized by glycerol-3-phosphate dehydrogenase (NAD+ → NADH) to dihydroxyacetone phosphate (DHAP). DHAP enters gluconeogenesis (via triose phosphate isomerase → glyceraldehyde-3-P → fructose-1,6-bisphosphate) or glycolysis.

**Tissue distribution:** Mainly liver and kidney (also intestine, lactating mammary gland, brown fat). Adipocytes have very little or no GK. As a result: - During fasting, adipose lipolysis (hormone-sensitive lipase) releases glycerol and free fatty acids. Glycerol travels to the liver, where GK traps it as glycerol-3-phosphate for gluconeogenesis. - Adipocytes make glycerol-3-phosphate for triglyceride esterification from DHAP, using glycerol-3-phosphate dehydrogenase. This depends on glucose uptake via GLUT4, which is insulin-dependent.

**Clinical significance (GK deficiency):** - Inheritance: X-linked recessive. The gene is *GK* at Xp21.3. - It is part of the Xp21 contiguous gene deletion syndrome. Nearby genes are *DMD* (Duchenne muscular dystrophy), *NR0B1/DAX1* (adrenal hypoplasia congenita) and others. Patients can have DMD, adrenal insufficiency and GK deficiency together. - Isolated GK deficiency can be asymptomatic or can cause episodic vomiting, lethargy and acidemia during fasting or illness. It can also cause hypoglycemia and hyperglycerolemia. - Lab artifact: Many triglyceride assays measure glycerol released after lipase hydrolysis. Elevated free glycerol therefore gives a falsely high triglyceride result (pseudo-hypertriglyceridemia). Urine glycerol is also elevated (glyceroluria).

**Board pearls:** - GK is the link between fat and carbohydrate metabolism. Glycerol is the only part of triglycerides that can be converted to glucose. Fatty acids (even-chain) cannot. - Glycerol kinase is not the same as glucokinase or glycerol-3-phosphate dehydrogenase. Don't confuse the GK step (uses ATP) with the G3P dehydrogenase step (uses NAD+). - Alcohol metabolism lowers the NAD+/NADH ratio. This diverts DHAP back to glycerol-3-phosphate and favors hepatic steatosis and impaired gluconeogenesis. - Liver steatosis: Excess glycerol-3-phosphate promotes triglyceride synthesis in the liver, which is relevant when glucose is abundant.