Decreased Postnatal Survival and Altered Body Weight Regulation in Procolipase-deficient Mice

Abstract

In vitro, pancreatic triglyceride lipase requires colipase to restore activity in the presence of inhibitors, like bile acids. Presumably, colipase performs the same function in vivo, but little data supports that notion. Other studies suggest that colipase or its proform, procolipase, may have additional functions in appetite regulation or in fat digestion during the newborn period when pancreatic triglyceride lipase is not expressed. To identify the physiological role of procolipase, we created a mouse model of procolipase deficiency. The Clps ؊/؊ mice appeared normal at birth, but unexpectedly 60% died within the first 2 weeks of life. The survivors had fat malabsorption as newborns and as adults, but only when fed a high fat diet. On a low fat diet, the Clps ؊/؊ mice did not have steatorrhea. The Clps ؊/؊ pups had impaired weight gain and weighed 30% less than Clps ؉/؉ or Clps ؉/؊ littermates. After weaning, the Clps ؊/؊ mice had normal rate of weight gain, but they maintained a reduced body weight compared with normal littermates even on a low fat diet. Despite the reduced body weight, the Clps ؊/؊ mice had a normal body temperature. To maintain their weight gain in the presence of steatorrhea, the Clps ؊/؊ mice had hyperphagia on a high fat diet. Clps ؊/؊ mice had normal intake on a low fat diet. We conclude that, in addition to its critical role in fat digestion, procolipase has essential functions in postnatal development and in regulating body weight set point.

Intestinal lipid absorption

“…The importance of colipase in the digestion of fat was indicated in a clinical report of steatorrhea in two brothers with a congenital absence of colipase, which indicated that the steatorrhea decreased with the administration of colipase (76). It has also been demonstrated in colipase-deficient mice (41), which, when placed on a high-fat diet, developed steatorrhea that was so severe that undigested lipids could be seen in their feces. When these mice were placed on a low-fat diet, their ability to digest fat returned to normal.…”

Physiological parameters governing the action of pancreatic lipase

“…In addition, when knock-out mice were fed a high-fat diet, they exhibited fat malabsorption through steatorrhoea (71) . Crystallographic analysis suggests that colipase binds to the non-catalytic, C-terminal domain of pancreatic lipase (5) .…”

“…Within this conversion, a five-amino acid fragment is lost. This pentapeptide, also referred to as enterostatin (70) , has been suggested to be important in appetite control in animal studies (71) . Due to shared pathways of secretion, a similar range of neurohumoral mediators is likely to affect up-and downregulation of procolipase release as that of pancreatic lipase (see above).…”

Effect of Long-term High-Fat Feeding on the Expression of Pancreatic Lipases and Adipose Tissue Uncoupling Proteins in Mice

“…have steatorrhea and decreased body weight (5). Colipase is secreted as a proform, procolipase, which is processed in the intestine to release colipase and a pentapeptide named enterostatin.…”