**3. Human dietary lipid digestion process and regulation of pancreatic fluid in healthy state**

Protein digestion begins in the stomach with the concomitant action of hydrochloric acid and pepsin, continues with pancreatic proteases in the duodenum, and finishes with numerous brush border peptidases located all over the small intestine (Fieker & al., 2011 as cited in Alpers, 1994). Starch digestion begins in the mouth with salivary amylase, continues with pancreatic amylase, and ends with several intestinal brush border oligosaccharidases (Fieker & al., 2011 as cited in Alpers, 1994). In contrast, the majority of lipid digestion and absorption occurs between the pylorus and the ligament of Treitz. Prior to this step, 5% to 40% of the dietary triglyceride acyl chains are released in the stomach by gastric lipase (Armand & al., 1994, 1996, 1999; Carrière & al., 1993b ; Hamosh, 1990) which continues its action in the duodenum together with pancreatic lipase until these enzymes are degraded by pancreatic proteases. Although a pH of 8 to 9 appears to be optimal for pancreatic lipase activity *in vitro*, bile salts allow the enzyme to work efficiently at a pH of 6 to 6.5 *in vivo* (Borgstrom, 1964; Carrière & al., 2005). HPL is responsible for the hydrolysis of 40% to 70% of triglycerides (Fig.2).

The pancreatic lipase-related 2 protein (hPLRP2), with a broader substrate specificity, hydrolyzes milk triglycerides (Berton & al., 2009) phospholipids (Jayne & al., 2002; Lowe, 2002; Thirstrup & al., 1994) galactolipids (Sias & al., 2004) and esters of lipid-soluble vitamins (Reboul & al., 2006). Carboxyl ester lipase (also called bile salt-stimulated lipase,

Emerging Approaches for the Treatment of

Fat Malabsorption due to Exocrine Pancreatic Insufficiency 277

Solomon, 1994). This gastric phase of digestion represents an important aspect in the overall postprandial regulation of pancreatic secretion. During the intestinal phase, enterohormones, such as CCK, together with neurotransmitters and neuropeptides further stimulate pancreatic secretion (Chey & Chang, 2001). Thus, digestive pancreatic enzyme response to a meal follows a specific pattern in which the degree and duration depend on nutrient composition, caloric content and physical properties of the meal. Enzyme secretion into the duodenum increases quickly reaching peak output within the first 20 to 60 minutes postprandially, then decreasing to a stable level before reaching an interdigestive level at the

end of the digestive period, ie, about 4 hours after meal intake (Keller & Layer, 2005).

leading role in the digestion of fat, which is the highest dietary source of calories.

occurs primarily in disorders directly affecting pancreatic tissue integrity (Table 3).

As previously described, the pancreas functions as the main factory for the digestive enzymes. The gland produces pancreatic juice that consists of a mixture of more than two dozen digestive enzymes in the pre-activated form, called zymogens. Zymogens are produced by acinar cells and mixed with a bicarbonate rich fluid that is produced by pancreatic ducts cells (Whitcomb & Lowe, 2007). Trypsin, chymotrypsin, amylase and lipase are responsible for the majority of the enzyme activity derived from the pancreas (Whitcomb & Lowe, 2007). Lipase is one of the most important enzymes because it plays a

Pancreatic exocrine insufficiency, partial or complete loss of digestive enzyme synthesis,

Pancreatic parenchymal disease

Chronic pancreatitis Post-necrotizing acute pancreatitis Cystic fibrosis Pancreatic cancers/tumors Autoimmune pancreatitis Extrapancreatic disease

Celiac disease Inflammatory bowel disease Diabetes mellitus Zollinger-Ellison syndrome

Postsurgical states

Gastric resection Whipple's pancreaticoduodenectomy Short bowel syndrome Bariatric surgeries (eg, gastric bypass)

Table 3. Conditions Causing EPI (adapted from Keller et al., 2009).

**4. Exocrine pancreatic insufficiency & fat malabsorption** 

Fig. 2. Schematic representation of the relative contributions of HGL and HPL to the overall digestion of dietary triacylglycerides. On a weight basis, the ratio of pancreatic lipase to gastric lipase total secretory outputs was found to be around four after 3 hours of digestion. The level of gastric hydrolysis was calculated to be 10% of the acyl chains released from the meal triglycerides. Gastric lipase remained active in the duodenum where it might still hydrolyze 7.5% of the triglyceride acyl chains. Hence, globally, during the whole digestion period, gastric lipase hydrolyzes 17.5% of all the triglyceride acyl chains. (Reproduced from Carrière & al., 1993b).

(BSSL)) will hydrolyze triglycerides, diglycerides, phospholipids, and esters of lipid-soluble vitamins and of cholesterol (Hui & Howles, 2002). Phospholipase A2 hydrolyzes phospholipids to lysophospholipids20 which is essential for an optimal absorption of lipid nutrients (Fieker & al., 2011, as cited in Tso, 1994).

Products generated during lipolysis are solubilized in bile salts–mixed micelles and liposomes (vesicles) which allow absorption across the intestinal villi. Once absorbed, the digested lipids are converted back to triglycerides, phospholipids, and esters of cholesterol and of lipid-soluble vitamins, then packaged as chylomicrons and transported through the thoracic duct into the systemic circulation for delivery to various sites throughout the body (Fieker & al., 2011, as cited in Tso, 1994).

To execute this digestive function, postprandial pancreatic juice secretion can increase up to 1 to 2 L per day in response to physiologic stimuli, mainly secretin and vagal output (Lee & Muallem, 2009). Appropriate enzyme delivery in the duodenum is allowed through a specific orchestration of the pancreatic fluid secretion during the fed state. In fact, during the gastric phase, digestion of proteins by pepsin and of triglycerides by gastric lipase generates amino acids and free fatty acids, respectively (Fieker & al., 2011, as cited in Alpers, 1994). When delivered through the pylorus, they become powerful stimulants of the cholecystokinin hormone (CCK) produced by the duodenal endocrine cells which stimulates pancreatic enzymes secretion and controls the gastric emptying rate. The acidic pH of the chyme entering the duodenum stimulates the release of secretin, which increases the secretion of water and bicarbonate ions from the pancreas (Fieker & al., 2011 as cited in

Fig. 2. Schematic representation of the relative contributions of HGL and HPL to the overall digestion of dietary triacylglycerides. On a weight basis, the ratio of pancreatic lipase to gastric lipase total secretory outputs was found to be around four after 3 hours of digestion. The level of gastric hydrolysis was calculated to be 10% of the acyl chains released from the meal triglycerides. Gastric lipase remained active in the duodenum where it might still hydrolyze 7.5% of the triglyceride acyl chains. Hence, globally, during the whole digestion period, gastric lipase hydrolyzes 17.5% of all the triglyceride acyl chains. (Reproduced from

(BSSL)) will hydrolyze triglycerides, diglycerides, phospholipids, and esters of lipid-soluble vitamins and of cholesterol (Hui & Howles, 2002). Phospholipase A2 hydrolyzes phospholipids to lysophospholipids20 which is essential for an optimal absorption of lipid

Products generated during lipolysis are solubilized in bile salts–mixed micelles and liposomes (vesicles) which allow absorption across the intestinal villi. Once absorbed, the digested lipids are converted back to triglycerides, phospholipids, and esters of cholesterol and of lipid-soluble vitamins, then packaged as chylomicrons and transported through the thoracic duct into the systemic circulation for delivery to various sites throughout the body

To execute this digestive function, postprandial pancreatic juice secretion can increase up to 1 to 2 L per day in response to physiologic stimuli, mainly secretin and vagal output (Lee & Muallem, 2009). Appropriate enzyme delivery in the duodenum is allowed through a specific orchestration of the pancreatic fluid secretion during the fed state. In fact, during the gastric phase, digestion of proteins by pepsin and of triglycerides by gastric lipase generates amino acids and free fatty acids, respectively (Fieker & al., 2011, as cited in Alpers, 1994). When delivered through the pylorus, they become powerful stimulants of the cholecystokinin hormone (CCK) produced by the duodenal endocrine cells which stimulates pancreatic enzymes secretion and controls the gastric emptying rate. The acidic pH of the chyme entering the duodenum stimulates the release of secretin, which increases the secretion of water and bicarbonate ions from the pancreas (Fieker & al., 2011 as cited in

Carrière & al., 1993b).

nutrients (Fieker & al., 2011, as cited in Tso, 1994).

(Fieker & al., 2011, as cited in Tso, 1994).

Solomon, 1994). This gastric phase of digestion represents an important aspect in the overall postprandial regulation of pancreatic secretion. During the intestinal phase, enterohormones, such as CCK, together with neurotransmitters and neuropeptides further stimulate pancreatic secretion (Chey & Chang, 2001). Thus, digestive pancreatic enzyme response to a meal follows a specific pattern in which the degree and duration depend on nutrient composition, caloric content and physical properties of the meal. Enzyme secretion into the duodenum increases quickly reaching peak output within the first 20 to 60 minutes postprandially, then decreasing to a stable level before reaching an interdigestive level at the end of the digestive period, ie, about 4 hours after meal intake (Keller & Layer, 2005).
