To determine mechanisms of elevated plasma trlglycerldes (TG) in patients with primary hypertrlglyceridemlas, simultaneous studies were carried out on kinetics of very low density llpoproteln-triglycerides (VLDL-TG) and synthesis of cholesterol and bile acids. Sixteen hypertrlglyceridemlc patients with familial combined hyperllpldemla (FCHL) and 12 patients with poorly classified, primary hypertriglyceridemia were studied, and their results were compared to a series of normal and obese subjects previously studied In our laboratory. The mean value for transport (synthesis) of VLDL-TG in patients with FCHL was about twice normal. Although the upper normal synthesis rates overlapped with transport rates of some patients with FCHL, It appeared that the major cause of hypertriglyceridemia in FCHL was an elevated production of VLDL-TG. However, the height of the plasma TG in FCHL patients also was influenced by Individual clearance capacities for VLDL-TG, and fractional clearance rates In several seemed particularly low. Synthesis rates for cholesterol and/or bile acids were high In several patients with FCHL, suggesting simultaneous overproduction of VLDL-TG and sterols; however, Increased synthesis of both was not observed In all the patients. Most patients with poorly classified hypertriglyceridemia had overproduction of VLDL-TG, but an apparent reduction in clearance was common. In these patients, Increased synthesis of cholesterol and bile acids was Infrequent. Our results indicate that abnormally high production of VLDL-TG seemed to be the major factor In causing primary hypertriglyceridemia, but that clearance capacity can play an important role In determining the severity of the TG elevation. (Arteriosclerosis 2:44-57, January/February 1982)
The DNA, RNA, and protein of apo C-II have been analyzed in a patient with apo C-II deficiency (apo C-IIHsbm). Markedly reduced levels of plasma and intrahepatic C-II apolipoprotein were demonstrated by immunoblotting and immunohistochemical analysis. Northern, slot blot, and in situ hybridization studies revealed low levels of a normal-sized apo C-II mRNA. No major rearrangement of the apo C-II gene was detected by Southern blotting. Sequence analysis of apo C-IT genomic clones revealed a G-to-C substitution within the donor splice site of intron II. This base substitution resulted in the formation of a new Dde I and loss of a Hph I restriction enzyme cleavage site. Amplification of the mutant sequence by the polymerase chain reaction and digestion with Dde I and Hph I restriction enzymes established that the patient was homozygous for the G-to-C mutation. This is the initial report of the DNA sequence of an abnormal apo C-II gene from a patient with deficiency of apo C-IL. We propose that this donor splice site mutation is the primary genetic defect that leads to defective splicing and ultimately to an apo C-II deficiency in this kindred.
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