Genetics and Biochemistry of Lipoprotein 
Lipase Deficiency 
Jean-Marc Lalouel, M.D., D.Sc. — Investigator 
Dr. Lalouel is also Professor of Human Genetics at the University of Utah School of Medicine. He obtained 
a medical doctorate, a master's degree in microbiology and genetics, and a doctorate of sciences in ge- 
netics at the University of Paris, France. He furthered his training as a postdoctoral fellow and a research 
associate with Newton Morton at the University of Hawaii and was Professor of Human Biology at the 
University of Paris before joining the faculty of the University of Utah. 
ABNORMAL lipoprotein concentrations in 
plasma are commonly observed in the rela- 
tives of patients with early coronary disease, 
yielding various patterns of hypercholesterol- 
emia and hypertriglyceridemia within families. 
Such complex phenotypes are thought to result 
either from the variable expression of a single- 
gene defect or the independent contribution of 
two or more genes. The genetic contribution to 
hyperlipidemia is further blurred by the fact that 
hormonal influences, diet, and habitus exen 
major influences on the regulation of lipid 
metabolism. 
Our investigation of a large kindred yielded 
preliminary results in support of the multiple- 
gene hypothesis. In this pedigree one gene ac- 
counts for hypercholesterolemia, but hypertri- 
glyceridemia depends on other factors. Among 
these, the gene encoding lipoprotein lipase 
(LPL) stood as a prime candidate. 
LPL plays a key role in the metabolism of di- 
etary and endogenous fat. Over 90 percent of di- 
etary fat is hydrolyzed by this enzyme in an initial 
step controlling its delivery to peripheral tissues. 
The enzyme is secreted by mesodermal cells such 
as adipocytes and muscle cells, but acts at a dis- 
tance from its site of synthesis. After secretion, it 
becomes anchored to the luminal surface of capil- 
laries in extrahepatic tissues by an ionic interac- 
tion with heparan sulfate. 
The enzyme needs apolipoprotein C-II as a co- 
factor to stimulate its catalytic activity. Also, di- 
merization is required. By binding to the surface 
of chylomicrons and very low density lipopro- 
teins, LPL hydrolyzes triglycerides of intestinal or 
hepatic origin, releasing free fatty acids for cellu- 
lar uptake where they can be used as fuel or re- 
esterified for storage. Thus the enzyme plays a 
key role in the distribution of fatty acids among 
various tissues. 
A host of factors regulate production of LPL, 
with stimulation by insulin, glucocorticoids, 
adenosine analogues, gastrin, and pancreozymin, 
and with inhibition by catecholamines, dibutyryl 
cAMP, and estrogens. While both the messenger 
RNA and the LPL gene have been characterized, 
little is known of the relationship between the 
enzyme's structure and its functional domains. 
These include a catalytic site and sites for lipid 
binding, heparin binding, and cofactor in- 
teraction. Other functional domains remain 
hypothetical. 
Defective functional enzyme is the diagnostic 
feature of a rare recessive chylomicronemia syn- 
drome, familial LPL deficiency. This condition is 
characterized by massive chylomicronemia in the 
fasting state, episodes of abdominal pain, recur- 
rent acute pancreatitis, and eruptive xanthomas. 
Deficiency of the enzyme can be demonstrated in 
adipose tissue or in plasma after injected heparin 
induces its release. 
The heterozygous state for LPL deficiency, by 
contrast, remains poorly characterized. Various 
reports document either normal lipids or moder- 
ate hypertriglyceridemia, and/or hypercholester- 
olemia, in relatives of deficient subjects. Could 
the heterozygous state, much more frequent than 
the homozygous, account for some form of the 
moderate to severe hypertriglyceridemia often 
noted in various clinical contexts? 
We were able to address this issue by investi- 
gating the relatives of a subject with classical LPL 
deficiency. After identification of the molecular 
defect present in the homozygous state in the 
proband, and after demonstration of its func- 
tional significance through in vitro mutagenesis 
and expression, we determined carrier status 
with respect to this mutation among 126 relatives 
of the patient. We contrasted clinical and bio- 
chemical parameters collected on these subjects. 
Our analysis revealed that the heterozygous 
state for this mutation indeed accounted for a 
common form of hypertriglyceridemia, accompa- 
nied by a sharp reduction of high-density lipo- 
protein cholesterol and subnormal levels of low- 
density lipoprotein cholesterol. These effects, 
however, were manifest only in subjects over 40. 
Our current hypothesis is that the heterozygous 
state imparts a latent, partial deficiency in the 
clearance of triglyceride-rich lipoproteins, 
which becomes manifest when triggered by other 
factors genetic or environmental. 
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