The regulation of sterol biosynthesis in leucocytes of subjects with familial hypercholesterolaemia

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Abstract
The regulation of sterol synthesis and 3‐hydroxy‐3‐methylglutaryl CoA reductase (HMG‐CoA reductase) activity in leucocytes has been studied in seventy‐five subjects of whom thirteen had familial hypercholesterolaemia (heterozygous). The activity of HMG‐CoA reductase in leucocytes was closely parallel to the incorporation of 14C‐acetate into sterols over a wide range of activities, suggesting that the enzyme is ratedetermining for the pathway. When six obese subjects were placed on an acaloric diet for 7 days sterol synthesis declined by 75% in adipocytes but was unaffected in leucocytes. A low cholesterol diet (< 250 mg/day) for 7 days did not affect sterol synthesis in either cell type.In subjects with familial hypercholesterolaemia (heterozygous) the enzyme tended to increase to higher levels than controls when leucocytes were incubated in a lipid‐deficient medium; but a more marked abnormality was a failure of suppression of the enzyme when leucocytes from affected subjects were returned for 8 h to a medium containing low‐density lipoprotein. In one kindred the index patient with severe heterozygous familial hypercholesterolaemia had a normally regulated enzyme whereas his affected siblings (brother and sister) showed incomplete suppression of the enzyme by low‐density lipoprotein.It is concluded that loss of regulation of HMG‐CoA reductase may be phenotypically linked to the origin of familial hypercholesterolaemia and in most cases provides a useful genetic marker for the disease.