Hepatic lipase, human

Selected entries from Methods in Enzymology [vol, page(s)] Detergent-resistant phospholipase Ai from Escherichia coll membranes, 197, 309 phospholipase Ai activity of guinea pig pancreatic lipase, 197, 316 purification of rat kidney lysosomal phospholipase Ai, 197, 325 purification and substrate specificity of rat hepatic lipase, 197, 331 human postheparin plasma lipoprotein lipase and hepatic triglyceride lipase, 197, 339 phospholipase activity of milk lipoprotein lipase, 197, 345. 

Ruel IL, Couture P, Cohn JS, Bensadoun A, Marcil M, Lamarche (2004) Evidence that hepatic lipase deficiency in humans is not associated with proatherogenic changes in HDL composition and metabolism. J Lipid Res 45 1528-1537... 

Abbreviations GcL, Geotrichum candidum lipase hPL, human pancreatic lipase RmL, Rhizomucor miehei lipase hHL, human hepatic lipase hLPL, human lipoprotein lipase hLAL, human lysosomal acid lipase hGL, human gastric lipase BAL, bile salt-activated lipase HSL, hormone-sensitive lipase CLP, colipase AChE, Torpedo cal omica acetylcholinesterase cDNA, complementary deoxyribonucleic acid VLDL, very low-density lipoprotein IDL, intermediate-density lipoprotein HDL, high-density lipoprotein apoC-II, apolipoprotein C-II. 

The human pancreatic lipase is homologous to two other lipases playing pivotal roles in lipoprotein metabolism lipoprotein lipase and hepatic lipase. Together these three proteins constitute the human lipase gene family. 

There are currently no published data regarding EL mass or activity levels in human plasma. Indeed, there has been relatively little study of phosphohpase activity in human plasma. Phospholipase activity increases after administration of heparin [24]. Some of the phospholipase activity in human plasma [25] has been attributed to lecithin-cholesterol acyltransferase (LCAT) [26] and hepatic lipase [27]. In the presence of inflammation, the secretory phospholipase A2 (sPLA2) may account for some of the plasma phosphohpase achvity and is also increased after heparin administration [28]. The contribuhon of endofhehal hpase to plasma phospholipase activity is unknown, but fhe decrease in post-heparin phosphohpase activity in EL knockout mice suggests that EL may contribute substantiaUy to plasma phosphohpase activity in humans. 

VLDL is metabolized via intermediate density lipoprotein (IDL) to LDL in the plasma by the action of lipoprotein lipase [72], Hepatic lipase may also contribute to the formation of TG-rich LDL particles [73], The increased production/decreased clearance of VLDL also may result in the increased production of precursors of small dense LDL (sd-LDL) particles [57,74,75], Such sd-LDL particles have been shown to contribnte to vascnlar diseases, as LDL receptors have a reduced affinity for sd-LDL, and sd-LDL are more vulnerable to oxidative modification [76-78], Numerous clinical stndies have shown increased CVD in subjects with high prevalence of sd-LDL [79], In animal models and in human diabetic conditions, sd-LDL levels are elevated [80,81] and snch accumulation appears to be accompanied by decreased paraoxonase 1 (PONl) activity. PONs are antioxidant enzymes that are known to detoxify H2O2 and lipid peroxides [82,83], The presence of PONl in lipoproteins also protects the... 

Hepatic lipase (HL) is synthesized de novo by macrophages in addition to the liver (437). Low HL activity in humans is associated with... 

Gonzalez-Navarro H, Nong Z, Freeman L, et al. Identification of mouse and human macrophages as a site of synthesis of hepatic lipase. J Lipid Res 2002 43 671-675. 

Yamagishi S, Abe T, Sawada T. Human recombinant interferon alpha-2a (r IFN alpha-2a) therapy suppresses hepatic triglyceride lipase, leading to severe hypertriglyceridemia in a diabetic patient. Am J Gastroenterol 1994 89(12) 2280. 

Purified apoA-II was shown by Jahn et al. (J2) to increase hepatic triglyceride lipase activity by threefold in vitro. Human plasma also activates hepatic triglyceride lipase activity, and it is a reasonable assumption that this activation is due to apoA-II. The physiological importance of this effect is not yet clear. 

Both PL and LPL require cofactors for full expression of activity (CLP and apoC-11, respectively) no such cofactor is necessary for HL. Derewenda and Cambillau (1991) postulated that, in the human lipase gene family of enzymes, the loops of the N-terminal domain, which exhibit the most pronounced variation in their amino acid sequences, may be responsible for conferring specificity with respect to cofactors. The structure of the lipase-procolipase complex (van Tilbeurgh et al., 1992 see above) does not support this hypothesis. However, in the case of LPL the structural basis of its interaction with apoC-11 may be quite different. Wong et al. (1991) and Davis et al. (1992) produced hybrid molecules by interchanging the C-terminal domains between the rat hepatic and lipoprotein lipases. Their HL chimera, made up of the HL N-terminal catalytic domain and the LPL C-terminal fragment, exhibited the salt-resistant catalydc properties characteristic of HL, but was... 

Fig. 1. Simplified schematic summary of the essential pathways for receptor-mediated human lipoprotein metabolism. The liver is the crossing point between the exogenous pathway (left-hand side), which deals with dietary lipids, and the endogenous pathway (right-hand side) that starts with the hepatic synthesis of VLDL. The endogenous metabolic branch starts with the production of chylomicrons (CM) in the intestine, which are converted to chylomicron remnants (CMR). Very-low-density lipoprotein particles (VLDL) are lipolyzed to LDL particles, which bind to the LDL receptor. IDL, intermediate-density lipoproteins LDL, low-density lipoproteins HDL, high-density lipoproteins LCAT, lecithinxholesterol acyltransferase CETP, cholesteryl ester transfer protein A, LDL receptor-related protein (LRPl) and W, LDL receptor. Lipolysis denotes lipoprotein lipase-catalyzed triacylglycerol lipolysis in the capillary bed.

The liver is clearly well equipped to utilize free fatty acids and to interconvert acetoacetate and hydroxybutyrate, but the virtual absence of 3-Oxoacid-CoA transferase and lipoprotein lipase means that any significant uptake of ketone bodies and triglycerides is restricted to extra-hepatic tissues. Heart and kidney contain the necessary enzymes to deal with all four fuels and this may reflect their high metabolic activity. Page and Williamson (1971) have shown that normal human brain has the capacity to utilize ketone bodies. 

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