Smooth endoplasmic reticulum or smooth ER is a sub-organelle with specialized functions in animal cells and plant cells. It is often associated with the tubule morphology of the endoplasmic reticulum.

The ER provides optimal conditions for synthesizing steroid hormones and lipids, such as phospholipids and triglycerides. Traditionally, lipid metabolism was considered to be a smooth ER function. However, there is no direct evidence to prove that rough ER is completely excluded from lipid synthesis. However, the absence of ribosomes and clustering of lipid synthesis enzymes at smooth ER regions make a good case for it to be a more efficient factory for lipid metabolism. Smooth ER synthesizes many primary membrane-building lipids such as phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, and sphingolipids.

Smooth ER is also involved in gluconeogenesis, a multi-step process for synthesizing glucose from non-carbohydrate precursors like pyruvate, lactate, etc., that primarily occurs in the liver and kidneys. The final step of this process converts glucose 6-phosphate to free glucose with the help of the enzyme glucose 6-phosphatase localized in the smooth ER lumen. A genetic deficiency of glucose-6-phosphatase leads to disturbed glucose homeostasis and glycogen accumulation in the liver and kidneys. The pathological condition that ensues is termed Von Gierke disease or Type 1 glycogen storage disease.

In addition, smooth ER also encompasses the cytochrome P450 family of enzymes that help to detoxify lipid-soluble drugs, barbiturates, and alcohol in the liver cells. Deficiency of the cytochrome P450 reductase enzyme results in congenital adrenal hyperplasia, characterized by severe skeletal and sexual ambiguity.