**1. Introduction**

The main purpose of the gastrointestinal tract is to digest and absorb nutrients (fat, carbohydrates, and proteins), micronutrients (vitamins and trace minerals), water, and electrolytes. Digestion involves both mechanical and enzymatic breakdown of food. Mechanical processes include chewing, gastric churning, and the to-and-fro mixing in the small intestine. Enzymatic hydrolysis is initiated by intraluminal processes requiring gastric, pancreatic, and biliary secretions. The final products of digestion are absorbed through the intestinal epithelial cells.

Malabsorption is a state arising from abnormality in absorption of food nutrients across the gastrointestinal (GI) tract. Depending on the abnormality, impairment can be of single or multiple nutrients leading to malnutrition and a variety of anaemias. Symptoms of malabsorption are varied because the disorder affects so many systems. General symptoms may include loss of appetite (anorexia), weight loss, fatigue, shortness of breath, dehydration, low blood pressure, and swelling (edema). Nutritional disorders may cause anemia (lack of iron, folate and vitamin B12), bleeding tendency (lack of vitamin K), or bone disease (lack of vitamin D). Gastrointestinal symptoms include flatulence, stomach distention, borborygmi (rumbling in the bowels), discomfort, diarrhea, steatorrhea (excessive fat in stool) and frequent bowel movements (Bai, 1998). Intestinal malabsorption can be due to : mucosal damage (enteropathy), congenital or acquired reduction in absorptive surface, defects of specific hydrolysis, defects of ion transport, impaired enterohepatic circulation or pancreatic insufficiency (Walker-Smith & al.,2002). This chapter will particularly focus on fat malabsorption, the overriding problem caused by severe pancreatic insufficiency.

Pancreatic insufficiency is a condition commonly associated with diseases such as pancreatitis or cystic fibrosis. Patients suffering from these pathologies show a shortage of the digestive enzymes necessary to break down food. Hence, a common feature of these diseases is a severe dietary malabsorption due to the poor hydrolysis of lipid in the lumen of small intestine. Digestive lipases are the key enzymes of fat digestion. The most common example of these enzymes is human pancreatic lipase. Nevertheless, the human lipases include the pre-duodenal lingual and gastric lipase, the extra-duodenal pancreatic, hepatic,

Emerging Approaches for the Treatment of

as well as native milk fat globules (Miled & al., 2000).

position of the triglyceride (Rogalska & al., 1990).

**2.1 Lingual lipase** 

**2.2 Gastric lipase** 

Fat Malabsorption due to Exocrine Pancreatic Insufficiency 271

The serous von Ebner glands of the tongue secrete lingual lipase in the saliva. Unlike rodents, lingual lipase is present in trace amounts in humans (Hamosh, 1990). Human lipase purified from lingual serous glands or gastric juice has a MW of 45 kDa to 51 kDa but tends to aggregate (MW 270-300 kDa and 500 kDa) and is highly hydrophobic (Hamosh, 1990). Lingual lipase has unique characteristics including an optimum activity at pH 4,5 – 5,4 and ability to catalyze reactions without bile salts (Hamosh & Scow, 1973). Lingual lipase breaks down short and medium chain saturated fatty acids and helps in their digestion. It has been stated that 10 to 30% of dietary fat is hydrolyzed in the stomach by lingual lipase. The enzyme uses a catalytic triad consisting of Aspartatic Acid-203 (Asp), Histidine-257 (His), and Serine-144 (Ser), to initiate the hydrolysis of a triglyceride into a diacyglyceride and a free fatty acid (Hamosh & Scow, 1973). Secreted in the buccal cavity, lingual lipase is one of the key components that make the digestion of milk fat in newborns possible. In humans lipolytic activity is present in gastric aspirates as early as 26 weeks of gestational age which is evidence enough for the fact that lingual lipase is present at birth (Hamosh, 1979). New born infants indeed secrete only low amounts of pancreatic lipase and bile salts and it has been demonstrated that pancreatic lipase alone does not readily hydrolyze a lipid emulsion

Gastric lipase (EC 3.1.1.3) is the predominant pre-duodenal lipase in humans. The enzyme is secreted in the gastric juice by the chief cells of fundic mucosa in the stomach (Moreau & al., 1988). The pre-duodenal enzyme was purified from human gastric aspirates and its Nterminal amino-acid sequence was determined. The amino-acid sequence from the isolated protein and the DNA sequence obtained from the cloned gene indicated that human gastric lipase consists of a 379 amino acid unglycosylated polypeptide with a molecular weight of 43 162 Da (Bodmer & al., 1987). However, native human gastric lipase (HGL) (molecular weight 50 kDa) is a highly glycosylated protein with four potential glycosylation sites (Bodmer & al., 1987). Human gastric and rat lingual lipase share a high degree of sequence homology and have identical gene organizations (Lohse & al., 1997). Gastric lipase belongs to the α/β-hydrolase-fold family. It possesses a classical catalytic triad (Ser-153, His-353, Asp-324) and an oxyanion hole (backbone NH groups of Gln-154 and Leu-67) analogous to serine proteases (Roussel & al., 1999). It has an optimum pH activity around 5.4, hydrolyzes long-, medium- and short-chain triacylglycerols and do not require bile acid or colipase for optimum enzymatic activity (Denigris et al., 1985). For many years, the exact physiological contribution of gastric lipase to the overall process of lipolysis was unknown. Carrière et al. (1993a) established, for the first time, that most of the HGL secreted in the stomach was still active in the duodenum. They estimated that the gastric lipase contribution in the hydrolysis of triglycerides is about 25 %. The stereoselectivity of HGL toward triglycerides was also investigated. It was clearly demonstrated that HGL shows a stereopreference for the sn-3

Hence, gastric lipase, together with lingual lipase, make up 30% of lipid hydrolysis occurring during digestion in the human adult, with gastric lipase contributing the most of the two acidic lipases. In neonates, these acidic pre-duodenal lipases are much more important, they

have the unique ability to initiate the degradation of maternal milk fat globules.

lipoprotein and the recently described endothelial lipase. In this chapter, a short basic overview of these fat-digesting enzymes and their physiological contribution to fat digestion is first presented. Thereafter, pathophysiology of fat malabsorption resulting from exocrine pancreatic insufficiency, clinical symptoms, incidence and diagnosis of the pathology are described as well.

Standard strategies for exocrine pancreatic insufficiency management are based on oral administration of porcine derived pancreatic extracts. Unfortunately, this approach is being unsatisfactory for many reasons. Greater attention has been paid over the last decade to optimize correction of fat malabsorption and essential fatty acid deficiency in order to improve the quality of life and extend the life span of patients with severe pancreatic insufficiency. Hence, we interestingly discuss herein drawbacks of therapeutic use of currently available lipase preparations before focusing mainly on research forces joined for the development of new oral enzyme substitution approaches and future promising opportunities to treat intestinal fat malabsorption caused by exocrine pancreatic insufficiency.
