The LPL gene in individuals with familial combined hyperlipidemia and decreased LPL activity.

Abstract

Familial combined hyperlipidemia (FCHL) is an oligogenic disorder, with family members having elevated apolipoprotein B-100 levels and either elevated plasma cholesterol or triglyceride levels or both. Obligate heterozygous parents of children with lipoprotein lipase (LPL) deficiency express a mild FCHL phenotype. Of patients with FCHL, 36% have diminished postheparin LPL activity and mass values that are comparable with those of obligate heterozygotes for LPL deficiency. It is hypothesized that heterozygosity for mutations in the LPL gene could contribute to FCHL in this subset of patients. Single-strand conformation polymorphism (SSCP) analysis, direct DNA sequencing, and Southern blot analysis were used to examine exons 1 through 9 and exon-intron junctions of the LPL gene in 20 patients with FCHL and low LPL activity and mass. One subject had a substitution (GAC->AAC) in exon 2, changing Asp to Asn. Two subjects had a previously undescribed "silent" substitution (GTG->GTA) in exon 3 at Val' 06 . Three patients had a premature termination at codon 447 in exon 9 resulting in F amilial combined hyperlipidemia (FCHL) was first described more than 20 years ago by Goldstein et al 1 and others. 2 ' 3 The central features of this disorder are elevations of plasma cholesterol, triglyceride (TG), or both in affected family members. Premature coronary heart disease is commonly found in these families, and FCHL is one of the major genetic causes of coronary heart disease. The phenotypic description of FCHL includes increased plasma apolipoprotein B-100 (apo B), small very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and low-density-lipoprotein (LDL) levels and decreased high-density lipoprotein (HDL) levels. 4 Despite intensive investigation, the genetic defects of this heterogeneous and possibly oligogenic truncation of the mature protein by two amino acids. In addition to SSCP analysis, exons 4,5, and 6, where almost all mutations in LPL-deficient patients have been found, were sequenced and no additional mutations were found. Southern blot analysis of the LPL gene revealed one subject with heterozygous loss of an EcoRI site but without an abnormality in Stu I restriction fragments; this mutation is therefore unlikely to be functionally significant. The substitutions identified at codons 9 and 447 have previously been found not to affect lipolytic activity when expressed in vitro. In summary, the findings suggest that mutations in the coding sequence of the LPL gene are an infrequent cause of FCHL Other mechanisms that regulate plasma LPL activity remain to be investigated in the pathogenesis of FCHL. Several lines of evidence support a role for abnormalities in the LPL gene or its regulation in some individuals with FCHL. Some investigators have found restriction fragment length polymorphisms and polymorphic microsatellites in the LPL gene to be associated with plasma lipoprotein levels.1820 Previous work from our laboratory has supported the concept that one type of FCHL is d...

Impaired Insulin-Stimulated Glucose Oxidation and Free Fatty Acid Suppression in Patients with Familial Combined Hyperlipidemia

“…Rare mutations in the lipoprotein lipase gene can cause FCHL 34 ; furthermore, lipid levels in FCHL patients have been associated with the apo A1-CIII-AIV gene cluster. 35 However, genetic background for FCHL remains unknown in most of the patients.…”

Severe hypertriglyceridemia, reduced high density lipoprotein, and neonatal death in lipoprotein lipase knockout mice. Mild hypertriglyceridemia with impaired very low density lipoprotein clearance in heterozygotes.

“…Humans with heterozygous LPL deficiency have a tendency to hypertriglyceridemia with advancing age, obesity, and diabetes, as well as during metabolic stress (10)(11)(12)(13)(14). LPL deficiency has been suggested as a cause of familial combined hyperlipoproteinemia (FCHL) a condition characterized by increased VLDL and LDL levels due at least in part to increased hepatic secretion of apo B-containing lipoproteins (15)(16)(17). Several groups have made LPL transgenic mice (18)(19)(20) and found that LPL overexpression causes decreased triglycerides and increased HDL.…”

Complex genetic contribution of the Apo AI-CIII-AIV gene cluster to familial combined hyperlipidemia. Identification of different susceptibility haplotypes.

“…Another candidate is the gene coding for the enzyme lipoprotein lipase (LPL) that is involved in the catabolism of trigyceride-rich lipoprotein particles. In FCH, a decreased LPL activity has been found in 30% of the affected individuals (17)(18)(19) that suggests that heterozygosity for LPL mutations might contribute to the lipid phenotype in FCH. However, mutations of the LPL gene (19)(20)(21)(22) appear to contribute to only a small fraction of FCH and by sibpair analysis we have excluded LPL as a major cause of FCH (Lusis, A.J., G.M.…”