Disease relevance of LIPC

• Ethnic differences in hepatic lipase and HDL in Japanese, black, and white Americans: role of central obesity and LIPC polymorphisms [1].
• In the present study, we have investigated the effects of the CETP promoter -1337 C>T and LIPC promoter -514 C>T polymorphisms on serum lipid profiles and risk of coronary atherosclerosis in 206 patients (154 males) with heterozygous FH (familial hypercholesterolaemia) [2].
• METHODS: Two genetic polymorphisms in LIPC (-514C-->T and +651A-->G) were determined by polymerase chain reaction and restriction analysis in 118 subjects of the ATOMIX (Atorvastatin in Mixed dyslipidemia) study who were randomized to treatment with either atorvastatin or bezafibrate and in 114 normolipidemic controls [3].
• In this study, we found that LIPC -514TT genotype and overweight status, when occurring together, were associated with a 3-fold increase in risk of preeclampsia among Peruvian women [4].
• HL (P < 0.05) and CETP activities (P < 0.05) were elevated in hyperthyroidism and reduced in hypothyroidism (P < 0.05, P < 0.01 respectively) and both were related to free T4 levels [5].

Psychiatry related information on LIPC

• CONCLUSIONS: Regular moderate physical activity in patients with type 2 diabetes led to an overall increase in HL, LPL, and LCAT [6].
• Acute alcohol withdrawal from a patient suffering from alcoholism with HLP led to a sharp increase of LPL with a simultaneous decrease of VLDL within 2 days and a more delayed increase of LDL, HDL2 and HTGL, all reaching normal values within 12 days after cessation of alcohol drinking [7].
• We validate the association of LIPC promoter variation with fasting serum HDL-c and present data supporting an interaction with physical activity implying an increased effect on HDL-c in vigorous physically active subjects carrying the -250 A allele [8].

High impact information on LIPC

• We conclude that oxandrolone increases the activities of postheparin plasma hepatic lipase and phospholipase A1 but has little influence on lipoprotein lipase [9].
• The effect of a synthetic steroid, oxandrolone, on total postheparin plasma lipolytic activity, postherpain hepatic lipase activity, lipoprotein lipase and phospholipase A1 was studied in seven patients with hypertriglyceridemia [9].
• Thereafter the cholesterol is esterified by lecithin:cholesterol acyltransferase; HDL is remodeled by cholesterol ester transfer protein (CETP) and hepatic lipase [10].
• Anecdotal examples of apparent modulation of atherosclerosis severity by lifestyle changes were also seen in other monogenic metabolic problems, such as hepatic lipase deficiency and Dunnigan-type familial partial lipodystrophy [11].
• Furthermore, the triglyceride content of low density lipoprotein, intermediate density lipoprotein and HDL, and the cholesterol content of intermediate density lipoprotein were found to be associated with variation at LIPC position -514 [12].

Chemical compound and disease context of LIPC

• The release of HL was maximal in healthy controls after 2-5 min, but in patients with liver disease the maximum was not reached until 15 min after heparin administration [13].
• It is plausible that a low LPL activity contributes to premature atherosclerosis as observed in insulin resistance and type 2 diabetes mellitus, but the effects of high HL activity and altered plasma cholesterol esterification on atherosclerosis development are uncertain [14].
• Postheparin plasma lipoprotein lipase and hepatic lipase in diabetes mellitus. Relationship to plasma triglyceride metabolism [15].
• Increase in hepatic lipase activity after testosterone substitution in men with hypogonadism of pituitary origin [16].
• Dyslipoproteinaemia in hypothyroidism of pituitary origin: effects of L-thyroxine substitution on lipoprotein lipase, hepatic lipase, and on plasma lipoproteins [17].

Biological context of LIPC

• Baseline Si was not associated with the LIPC genotypes [18].
• RECENT FINDINGS: Twenty to 30% of individual variation of hepatic lipase activity is accounted for by the presence of a common polymorphism in the promoter region (-514 C to T) of the hepatic lipase gene (LIPC) [19].
• The LIPC -514C allele frequency was 0.516 (blacks) and 0.796 (whites) [18].
• PGC-1alpha is capable of stimulating the HNF4alpha-dependent transactivation of the LIPC promoter [20].
• Reporter analysis showed that HNF4alpha directly regulates the LIPC promoter via two newly identified direct repeat elements, DR1 and DR4 [20].

Anatomical context of LIPC

• Hepatic lipase (HL) on the surface of hepatocytes and endothelial cells lining hepatic sinusoids, the adrenal glands, and the ovary hydrolyzes triglycerides and phospholipids of circulating lipoproteins [21].
• 125I-Labeled HL is rapidly internalized and degraded by HepG2 cell lines, and approximately 70% of the cellular internalization and degradation is blocked by either exogenously added RAP or anti-LRP IgG [22].
• Mouse fibroblasts that lack LRP display a greatly diminished capacity to internalize and degrade HL when compared to control fibroblasts [22].
• HL activity was negatively correlated with total and coronary artery calcified lesion volume (r = -.55 to .57, P < .05) [23].
• Effect of thyroid dysfunction on high-density lipoprotein subfraction metabolism: roles of hepatic lipase and cholesteryl ester transfer protein [5].

Associations of LIPC with chemical compounds

• There was no consistent relationship between the population mean plasma HDL cholesterol concentration and the population LIPC -480T frequency [24].
• However, we cannot exclude the participation of these genes, or the LIPC and LPL genes, as minor susceptibility loci in the expression of FCHL, or the TG or elevated total cholesterol (TC) traits in our families [25].
• Common variation in promoters of both genes, LIPC -514C > T and APOC3 -482C > T, respectively, have been shown to affect plasma lipids and lipoproteins and glucose tolerance [26].
• In summary, HDL metabolism was altered in thyroid dysfunction, and the effect of thyroid hormone on HDL was mediated mainly via its effect on HL activity [5].
• Plasma activities of lipoprotein lipase, hepatic lipase and lecithin: cholesterol acyltransferase in patients considered for parenteral nutrition with fat emulsion [27].

Physical interactions of LIPC

• Hepatic lipase can also mediate binding of remnants to LRP, for which it has high affinity [28].
• HL maturation occurs in the ER and is strongly dependent on binding to calnexin in the early co-/post-translational stages [29].
• Heparan sulfate has been further implicated in presentation and stabilization of lipoprotein lipase and hepatic lipase on cell surfaces and in the transport of lipoprotein lipase from extravascular cells to the luminal surface of the endothelia [30].

Enzymatic interactions of LIPC

• HTGL hydrolyzed triolein substrate at a rate much slower than LPL, and produced mainly free oleate with little monooleate [31].

Regulatory relationships of LIPC

• In addition, apoA-II enhances the ability of reconstituted LpA-I particles to inhibit VLDL-TG hydrolysis by HL [32].
• Under these conditions HL promoted marked reduction in HDL particle size in a process dependent on the concentration of VLDL triacylglycerol while LPL was virtually without effect [33].
• ARP-1 displaces HNF4alpha from the DR1 site and blocks its ability to activate the LIPC promoter [20].
• Apolipoprotein E enhances hepatic lipase-mediated hydrolysis of reconstituted high-density lipoprotein phospholipid and triacylglycerol in an isoform-dependent manner [34].
• We have shown previously that apolipoprotein A-I (apoA-I) and apoA-II have a major influence on the kinetics of HL-mediated phospholipid and triacylglycerol hydrolysis in well-characterized, homogeneous preparations of spherical rHDL [Hime, N. J., Barter, P. J., and Rye, K.-A. (1998) J. Biol. Chem. 273, 27191-27198] [35].

Other interactions of LIPC

• The latter correlated positively with LPL activity and HDL2 levels, and, inversely, with HL activity, lipemia, and triglyceride content of HDL2 [36].
• There was no change in LPL, HTGL, or LCAT [37].
• The effects of r-HDL morphology and size on HL activity were studied on r-HDL made of palmitoyloleoyl-PC, unesterified cholesterol, cholesteryl ester, and apolipoprotein AI [38].
• ApoA-II appears to increase HL association with HDL and inhibits lipid hydrolysis [32].
• Crosslinking experiments confirmed the binding of HL to LRP on the cell surface [39].

Analytical, diagnostic and therapeutic context of LIPC

• Genotyping at position -250 of the LIPC gene was performed with PCR amplification, DraI enzyme digestion, and gel electrophoresis in 490 subjects with IGT whose DNA was available [40].
• The higher HLA in the WA men remained after adjustment for the LIPC polymorphism's effect on HLA (P = 0.037) but was erased after adjustment for waist-to-hip-ratio (P = 0.46) [1].
• No significant association was found between LIPC -480T and plasma HDL cholesterol or apolipoprotein AI concentration, after adjusting for covariates including gender and body mass index [24].
• In cell culture experiments HL enhanced the uptake of 125I-LDL at both 4 and 37 degreesC [21].
• Effects of hormone replacement therapy and hepatic lipase polymorphism on serum lipid profiles in postmenopausal Japanese women [41].

References