Inheritable abnormal lipoprotein metabolism in Werner's syndrome similar to familial hypercholesterolaemia

Abstract

Studies were made on the abnormality of lipoprotein metabolism and its cause in 10 patients with Werner's syndrome. Seven of the 10 patients had hypercholesterolaemia (above 250 mg dl-I). Six of the seven patients with hypercholesterolaemia had thickened Achilles' tendons (> 9 mm). A significant positive correlation (P < 0.01) was found between the serum total cholesterol levels and the thickness of Achilles' tendons in these 10 patients, suggesting that the substance precipitated in the thickened tendons is derived from serum cholesterol. Some first-degree relatives of three patients with both hypercholesterolaemia and xanthoma-like thickening of Achilles' tendons also suffered from hypercholesterolaemia. Moreover, the low density lipoprotein (LDL) receptor activities in peripheral lymphocytes of five patients with both hypercholesterolaemia and xanthoma-like tendons were significantly (P < 0.001) lower than those of controls, whereas the LDL receptor activities of two patients without hypercholesterolaemia were almost the same as those of controls. These findings suggest that, at least these five patients with lower lymphocyte LDL receptor activities, and probably another patient with both hypercholesterolaemia and xanthoma-like thickening of Achilles' tendons suffered from familial hypercholesterolaemia (FH). If this is the case, this high frequency of association of Werner's syndrome with FH (in six of 10 patients) suggests some relationship between these two diseases.

Management guideline for Werner syndrome 2020 1. Dyslipidemia and fatty liver associated with Werner syndrome

“…As to hyper‐LDL cholesterolemia, Yokote and Mori et al . reported that thickened Achilles tendon and hypercholesterolemia occurred in six out of 10 Werner syndrome patients in their facilities, 47 and five of them showed a decrease in the LDL receptor activity; 51 thus, it might be plausible that Werner syndrome itself possesses some sort of mechanism to decrease the LDL receptor activity. Given that an increased LDL cholesterol level is a disease‐specific postnatal feature in Werner syndrome, it might be possible to assume that hypercholesterolemia in Werner syndrome patients has a risk equivalent to familial hypercholesterolemia considering the notion of cumulative LDL cholesterol, which has recently been proposed.…”

Role of phospholipase A2 in expression of the scavenger pathway in cultured aortic smooth muscle cells stimulated with phorbol 12-myristate 13-acetate

“…Assay of acetylated LDL degradation Degradation and binding of 1251-labelled acetylated LDL (125I1 aLDL) or 125I-LDL were assayed as reported [15,16]. Briefly, LDL was obtained from the serum of normal volunteers, and acetylated and iodinated as reported [17,18].…”

“…Stimulation time (h) Figure 3 Effect of length of stimulation period with PMA on degradation of 51l-aLDL by medial SMC Medial SMC were incubated with 1 x 10-8 M PMA for the indicated periods and then after changing the medium with 10 #cg/Ml 125 I-aLDL as described in the legend of degradation activities were as follows; without PMA, 0; I x 10-1°M PMA, 2.81 +0. 16 (n = 3); 1 x 10-9 M PMA, 2.76 (n = 2); 1 x 10-1 M PMA 5.39+0.12 (n = 3); 1 x 10-7 M PMA, 0.62 + 0.28 (n = 3) ,ug/mg of cell protein (mean _ S.D.). PMA at I X 10-7 M had less effect on the degradation activity of SMC, although it caused no injury of the cells detectable by microscopy or by the Trypan Blue exclusion test.…”

Metabolic and Phenotypic Differences between Mice Producing a Werner Syndrome Helicase Mutant Protein and Wrn Null Mice

“…Overall, such mutant mice have a 10–15% decreased of their mean life span [ 17 , 18 ]. Of relevance, increased oxidative stress has been described for WS subjects in addition to abnormal metabolic phenotypes [ 19 – 21 ]. In addition to the metabolic abnormalities found in Wrn Δhel/Δhel mice, microscopic analysis of tissues revealed three other major changes; increased levels of visceral fat tissues, defenestration of liver sinusoidal endothelial cells (an increasingly recognized morphological change associated with normal aging [ 22 ]), liver steatosis [ 23 ], and aortic stenosis [ 24 ] followed by cardiac fibrosis [ 16 ].…”