Disease relevance of Lipc

• DISCUSSION: This use of reciprocal hemizygosity analysis in mammals, which, to our knowledge, is the first reported, reveals its power to detect previously unknown effects of Lipc on obesity [1].
• Mice doubly deficient in apo E and hepatic lipase have more pronounced hypercholesterolemia, even though remnants do not accumulate appreciably in mice deficient in hepatic lipase alone [2].
• Mild dyslipidemia in mice following targeted inactivation of the hepatic lipase gene [3].
• In these mice, hypertriglyceridemia results from the inhibition of lipoprotein lipase and hepatic lipase activities by hapoA-II carried on VLDL [4].
• We have investigated the role of hepatic lipase (HL) in remnant lipoprotein metabolism independent of lipolysis by using recombinant adenovirus to express native and catalytically inactive HL (HL-145G) in apolipoprotein (apo)E-deficient mice characterized by increased plasma concentrations of apoB-48-containing remnants [5].

High impact information on Lipc

• This is most likely due to reduced activity of the HDL-catabolic enzyme hepatic lipase (Lipc) and increased expression of HDL-cholesterol esterifying enzyme lecithin:cholesterol acyl transferase (Lcat) [6].
• We found that expression of HL by macrophages enhances early aortic lesion formation in both apoE-KO and LCAT-Tg mice, without changing the plasma lipid profile, lipoprotein lipid composition, or HL and lipoprotein lipase activities [7].
• Hepatic lipase expression in macrophages contributes to atherosclerosis in apoE-deficient and LCAT-transgenic mice [7].
• HL does, however, enhance oxidized LDL uptake by peritoneal macrophages [7].
• We used bone marrow transplantation (BMT) to generate apoE-KO and apoE-KO x HL-KO mice, as well as LCAT-Tg and LCAT-Tg x HL-KO mice, chimeric for macrophage HL gene expression [7].

Chemical compound and disease context of Lipc

• A locus for hepatic lipase activity was co-incident with the body fat and total cholesterol loci on chromosome 7, providing a possible mechanism linking plasma lipoproteins and obesity [8].

Biological context of Lipc

• No interaction between Lipc and chromosome 7 was demonstrated [1].
• The CLD mutation allows synthesis and glycosylation of HL, but blocks activation of the lipase [9].
• We have further characterized the abnormal lipoprotein phenotype in young hepatic lipase-deficient mice and have found more pronounced elevations of high density lipoproteins associated in particular with a 5-fold increase in plasma concentrations of apolipoprotein E [10].
• Hepatic lipase may prevent such vesicular lipoproteins from accumulating in apo E-deficient mice by hydrolyzing phosphatidyl choline as scavenger receptor B1 removes the cholesteryl esters and by gradual endocytosis of lipoproteins bound to hepatic lipase on the surface of hepatocytes [2].
• To extend this observation, the HL transgene was expressed in human apoB transgenic (huBTg) and apoE-deficient (apoE-/-) mice, both of which have high plasma levels of apoB-containing lipoproteins [11].

Anatomical context of Lipc

• Immunofluorescence studies located HL mostly outside of cells in liver, liver cell cultures and incubated adrenal tissue of normal and cld/cld mice and mostly inside of cells in liver cell cultures and adrenal tissues treated with monensin (to block secretion of protein) [9].
• LPL is synthesized in heart, muscle and adipose tissue, while HL is synthesized primarily in liver [9].
• Immunofluorescence studies showed HL was present in extracellular space, but not in cells, in liver and adrenal of both normal and cld/cld mice [12].
• Two loci for body fat and lipoprotein levels (on central and distal chromosome 2) coincided with a locus having strong effects on hepatic lipase activity, an activity associated with visceral obesity and lipoprotein levels in humans [13].
• HL activity is not needed for the SR-BI-mediated HDL-cholesteryl ester uptake by rat adrenal glands [14].

Associations of Lipc with chemical compounds

• RESULTS: We show here that mice lacking both endogenous HL and LDL receptor (HL-/-:LDLR-/-) dramatically increased their plasma triglyceride-rich lipoproteins and their remnants as a consequence of reduced liver uptake [15].
• Heparin had no significant effect on plasma hepatic lipase activity in defective mice [16].
• Mice lacking both HL and apoE (hhee) have a plasma total cholesterol of 917 +/- 252 mg/dl (n = 24), which is 184% that of mice lacking only apoE (HHee; 497 +/- 161 mg/dl, n = 20, p < 0. 001) [17].
• Attenuated corticosterone response to chronic ACTH stimulation in hepatic lipase-deficient mice: evidence for a role for hepatic lipase in adrenal physiology [18].
• Fenofibrate did not induce any change in hepatic lipase activity [19].

Regulatory relationships of Lipc

• These findings indicate that SR-BI expression may be influenced by changes in HL activity [14].
• HL knockout mice had a similar prevalence of gallstone formation as compared with control mice when both strains were fed with a lithogenic diet [20].
• Pre-injection of lactoferrin into normal mice inhibited the plasma clearance of both non-lipolyzed chylomicrons and chylomicrons lipolyzed by HL [21].

Other interactions of Lipc

• Thus, the cld mutation appears not to globally disrupt the secretion of all N-linked glycoproteins, but rather selectively impairs LPL and HL at points essential to their normal intracellular transport and secretion [22].
• Combined hyperlipidemia/hyperalphalipoproteinemia associated with premature spontaneous atherosclerosis in mice lacking hepatic lipase and low density lipoprotein receptor [15].
• Thus, the CLD mutation allows secretion of inactive HL by liver and adrenals [9].
• Our findings indicate that LPL, HL and pancreatic lipase, although closely related, are processed differently [9].
• The action of hepatic lipase on apoA-I-containing lipoproteins may facilitate the SR-BI-mediated uptake of HDL lipid [23].

Analytical, diagnostic and therapeutic context of Lipc

• Plasma levels of CETP, lipoprotein lipase, and hepatic lipase were not changed by castration [24].
• Adrenal SR-BI mRNA and protein are also increased and cholesterol stores decreased in female mice with knockout of hepatic lipase, and enzyme previously shown to increase selective uptake in cell culture [23].
• HL and PLTP activities did not differ from those in the control group during the whole experimental period [25].
• Immunoblotting demonstrated high levels of human HL in postheparin plasma of both apoE-/-,hHLTg+/0 and apoE-/-,HL-CAT+/0 mice [11].
• HL was localized by immunohistochemistry to the liver and to the adrenal cortex [11].

References