Carboxyl Ester Lipase Deficiency Exacerbates Dietary Lipid Absorption Abnormalities and Resistance to Diet-induced Obesity in Pancreatic Triglyceride Lipase Knockout Mice

Abstract

Despite the fundamental importance that digestion, absorption, and subsequent trafficking of dietary fat, fat soluble vitamins, and cholesterol play in health and disease, details of the molecular events involved in these processes remain poorly described. Dietary lipids, such as triacylglycerol (TAG), 4 phospholipids, cholesteryl esters, and retinyl esters must be cleaved by intestinal hydrolases before absorption. Thus, lipid hydrolases derived from the pancreas are central in the digestion and absorption of these dietary components. The most abundant lipolytic enzymes secreted by the pancreas include pancreatic triglyceride lipase (PTL) and carboxyl ester lipase (CEL, formerly named cholesterol esterase). The principal enzyme involved in the hydrolysis of dietary TAG, thereby mediating its absorption, has generally been accepted as PTL. In contrast, the major role of CEL in the digestive tract is generally ascribed to digestion of cholesteryl esters and retinyl esters before their absorption.Recent studies with genetically modified mouse models designed to critically examine the role of pancreatic lipolytic enzymes in lipid digestion and transport revealed some unexpected findings. First, TAG absorption was altered very little, but free cholesterol absorption was reduced substantially in PTL Ϫ/Ϫ mice (1). Second, whereas CEL Ϫ/Ϫ mice displayed dramatically reduced cholesteryl ester hydrolysis and absorption as expected (2), retinyl ester digestion and absorption were similar between CEL ϩ/ϩ and CEL Ϫ/Ϫ mice (3). The decrease in cholesterol absorption observed in the PTL Ϫ/Ϫ mice was attributed to PTL deficiency delaying dietary fat absorption to the distal small intestine (ileum) where intestinal cholesterol uptake is less efficient (4, 5). However, the nearly normal absorption of TAG and retinyl esters in PTL Ϫ/Ϫ and CEL Ϫ/Ϫ mice suggested that more than one enzyme participates in the digestion of these lipids in vivo. In vitro studies examining lipolytic activities in pancreatic extracts from PTL Ϫ/Ϫ and CEL Ϫ/Ϫ mice provided insights to the identity of enzymes responsible for TAG and retinyl ester hydrolysis. In these studies pancreatic extracts from PTL Ϫ/Ϫ mice were shown to contain robust TAG hydrolytic activity, albeit at lower levels than those observed in pancreatic extracts from wild type mice. Importantly, the TAG hydrolytic activity in PTL Ϫ/Ϫ pancreas was dependent on the presence of taurocholate, whereas taurodeoxycholate was found to be ineffective (1). This selectivity of trihydroxylated bile salt for TAG hydrolytic activity in PTL Ϫ/Ϫ pancreas is consistent with the trihdroxy-but not dihydroxy-bile salt dependence of CEL (6), thus * This work was supported by National Institutes of Health Grant DK067416.The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Phytosterol stearate esters elicit similar responses on plasma lipids and cholesterol absorption but different responses on fecal neutral sterol excretion and hepatic free cholesterol in male Syrian hamsters

“…However, because intact phytosterol esters do not incorporate into micelles or affect cholesterol solubility within mixed micelles in vitro [34], unhydrolyzed phytosterol esters may affect cholesterol absorption independent of micelles by creating a lipid phase in which cholesterol becomes trapped. Indirect evidence for this can be inferred by decreased cholesterol absorption in triglyceride lipase knockout mice fed a high-cholesterol, high-fat diet [35]. As we previously observed, the superior cholesterol lowering of presumably intact 5% stearate-enriched phytosterol esters compared with a completely hydrolyzed treatment (consumed as 3.0% free phytosterols and 2.0% stearic acid) [12] supports the presence of a separate phytosterol stearate mechanism.…”

Physiological Roles of Group X-secreted Phospholipase A2 in Reproduction, Gastrointestinal Phospholipid Digestion, and Neuronal Function

“…2B). This speculation is in line with the view that, even if dietary fat digestion and absorption are completed, their delay leads to changes in the spatiotemporal distribution of fat absorption in the gastrointestinal tract that can be linked to decreased adipose fat storage and altered metabolic efficiency, as evidenced by ablation of pancreatic and carboxyl ester lipases (59) or monoacylglycerol acyltransferase (MGAT2), a major fat re-esterification enzyme in the proximal intestine that is coupled with transport of lipids to chylomicron for distribution to peripheral tissues (63).…”

“…Hydrolysis of phospholipids by PLA 2 on the surface of lipid emulsion is required before digestion of triglycerides, a major lipid nutrient (58). Pancreatic lipase and carboxyl ester lipase work together to mediate the hydrolysis and subsequent absorption of a large portion of dietary triglycerides, and reduced lipid absorption efficiency due to inactivation of these lipase genes results in protection against diet-induced obesity (59). For a long time, sPLA 2 -IB, a pancreatic sPLA 2 , has been believed to be the sole sPLA 2 isoform that works in the digestion of dietary phospholipids in the gastrointestinal tract.…”

Expression of Pla2g2a prevents carcinogenesis in Muc2‐deficient mice

“…(40,41) A third gene analyzed by qRT-PCR is Cel (carboxyl ester lipase, down-regulated in the arrays and down-regulated by 2.9 fold in qRT-PCR), a secreted lipase found in the gastrointestinal tract that is involved in fat digestion and absorption, and insulin and cholesterol metabolism, and Cel knockout mice are resistant to obesity in mice caused by high fat diets. (42)(43)(44) Other Pla2g2a target intestinal enzymes confirmed by qRT-PCR were Clps (pancreatic colipase, down-regulated 4-fold), a type-2 diabetes susceptibility gene; (45) Ela2a (a GI tract elastase down-regulated 5.9-fold) (46) and Ctrb1 (chymotrypsinogen B1, down-regulated 24 fold). (47) Although the role of each of these Pla2g2a target genes in susceptibility to intestinal neoplasia is unclear, considered together these highly significant target genes demonstrate that Pla2g2a exerts a strong influence on genes involved in intestinal energy metabolism and inflammation that may work in unison to maintain intestinal homeostasis.…”