Hypertriglyceridemia is common in the general population, but its mechanism is largely unknown. In previous work human apo CIII transgenic (HuCIIITg) mice were found to have elevated triglyceride levels. In this report, the mechanism for the hypertriglyceridemia was studied. Two different HuCIIITg mouse lines were used: a low expresser line with serum triglycerides of -280 mg/dl, and a high expressor line with serum triglycerides of -1,000 mg/dl. Elevated triglycerides were mainly in VLDL. VLDL particles were 1.5 times more triglyceride-rich in high expressor mice than in controls. The total amount of apo CIII (human and mouse) per VLDL particle was 2 and 2.5 times the normal amount in low and high expressors, respectively. Mouse apo E was decreased by 35 and 77% in low and high expresser mice, respectively. Under electron microscopy, VLDL particles from low and high expresser mice were found to have a larger mean diameter, 55.2±16.6 and 58.2±17.8 nm, respectively, compared with 51.0±13.4 nm from control mice. In in vivo studies, radiolabeled VLDL fractional catabolic rate (FCR) was reduced in low and high expresser mice to 2.58 and 0.77 pools/h, respectively, compared with 7.67 pools/h in controls, with no significant differences in the VLDL production rates. In an attempt to explain the reduced VLDL FCR in transgenic mice, tissue lipoprotein lipase (LPL) activity was determined in control and high expresser mice and no differences were observed. Also, VLDLs obtained from control and high expresser mice were found to be equally good substrates for purified LPL
Behçet disease is a multisystemic and chronic inflammatory disorder of unknown cause that is characterized by recurrent oral and genital ulcerations, ocular manifestations, and additional clinical manifestations in multiple organ systems. Behçet disease involving the chest can manifest as a wide spectrum of abnormalities. Although conventional chest radiography is commonly used for initial assessment, spiral computed tomography can demonstrate the entire spectrum of thoracic manifestations of Behçet disease, including abnormalities of the vessel lumen and wall, perivascular tissues, lung parenchyma, pleura, and mediastinal structures. Aneurysms of the pulmonary arteries, with or without thrombosis, are a typical manifestation of Behçet disease. Other manifestations include thrombosis, vasculitis, hemorrhage, infarction, and inflammation. Familiarity with these manifestations can be useful in the diagnosis of Behçet disease, helping to determine the cause of symptoms in patients who present with hemoptysis and guide the choice of appropriate therapy.
Lipoprotein lipase (LPL), the rate-limiting enzyme in triglyceride hydrolysis, is normally not expressed in the liver of adult humans and animals. However, liver LPL is found in the perinatal period, and in adults it can be induced by cytokines. To study the metabolic consequences of liver LPL expression, transgenic mice producing human LPL specifically in the liver were generated and crossed onto the LPL knockout (LPL0) background. LPL expression exclusively in liver rescued LPL0 mice from neonatal death. The mice developed a severe cachexia during high fat suckling, but caught up in weight after switching to a chow diet. At 18 h of age, compared with LPL0 mice, liver-only LPL-expressing mice had equally elevated triglycerides (10,700 vs. 14,800 mg/dl, P ϭ NS), increased plasma ketones (4.3 vs. 1.7 mg/dl, P Ͻ 0.05) and glucose (28 vs. 15 mg/dl, P Ͻ 0.05), and excessive amounts of intracellular liver lipid droplets. Adult mice expressing LPL exclusively in liver had slower VLDL turnover than wild-type mice, but greater VLDL mass clearance, increased VLDL triglyceride production, and three-to fourfold more plasma ketones. In summary, it appears that liver LPL shunts circulating triglycerides to the liver, which results in a futile cycle of enhanced VLDL production and increased ketone production, and subsequently spares glucose. This may be important to sustain brain and muscle function at times of metabolic stress with limited glucose availability. ( J. Clin. Invest. 1998. 102:893-901.)
Several types of transgenic mice were used to study the influence of hypertriglyceridemia and cholesteryl ester transfer protein (CETP) expression on high density lipoprotein (HDL) levels, particle sizes, and metabolism. The presence of the CETP transgene in hypertriglyceridemic human apo CIII transgenic mice lowered HDL-cholesterol (HDL-C) 48% and apolipoprotein (apo) A-I 40%, decreased HDL size (particle diameter from 9.8 to 8.8 nm), increased HDL cholesterol ester (CE) fractional catabolic rate (FCR) 65% with a small decrease in HDL CE transport rate (TR) and increased apo A-I FCR 15% and decreased apo A-I TR 29%. The presence of the CETP transgene in hypertriglyceridemic mice with human-like HDL, human apo A-I apo CIII transgenic mice, lowered HDL-C 61% and apo A-I 45%, caused a dramatic diminution of HDL particle size (particle diameters from 10.3 and 9.1 to 7.6 nm), increased HDL CE FCR by 107% without affecting HDL CE TR, and increased apo A-I FCR 35% and decreased apo A-I TR 48%. Moreover, unexpectedly, hypertriglyceridemia alone in the absence of CETP was also found to cause lower HDL-C and apo A-I levels primarily by decreasing TRs. Decreased apo A-I TR was confirmed by an in vivo labeling study and found to be associated with a decrease in intestinal but not hepatic apo A-I mRNA levels. In summary, the introduction of the human apo A-I, apo CIII, and CETP genes into transgenic mice produced a high-triglyceride, low-HDL-C lipoprotein phenotype. Human apo A-I gene overexpression caused a diminution of mouse apo A-I and a change from monodisperse to polydisperse HDL. Human apo CIII gene overexpression caused hypertriglyceridemia with a significant decrease in HDL-C and apo A-I levels primarily due to decreased HDL CE and apo A-I TR but without a profound change in HDL size. In the hypertriglyceridemic mice, human CETP gene expression further reduced HDL-C and apo A-I levels, primarily by increasing HDL CE and apo A-I FCR, while dramatically reducing HDL size. This study provides insights into the genes that may cause the high-triglyceride, low-HDL-C phenotype in humans and the metabolic mechanisms involved. (J.
We have previously described two transgenic mouse lines, one heterozygous for the human apo A-I gene and the other heterozygous for a human cholesteryl ester transfer protein (CETP) minigene driven by the mouse metallothionein-I gene promoter. In the current study, these two lines were crossed producing control, HuCETPTg, HuAITg, and HuAICETPTg mice to study the influence of CETP on HDL cholesterol levels, particle size distribution, and metabolism in animals with mouse and human-like HDL. In the HuCETPTg and HuAICETPTg animals, zinc induction approximately doubled plasma CETP activity, with no activity in plasma from the control and HuAITg animals. The only significant effect of CETP on lipoprotein subfraction cholesterol concentrations was for HDL-C. Compared to control animals, HuCETPTg animals had lower HDL-C, 20% before and 35% after Zn induction, and compared to HuAITg animals, HuAICETPTg animals had lower HDL-C, 35% before and 66% after Zn induction. Control and HuCETPTg HDL consist primarily of a single size population with a mean diameter of 10.00±0.10 nm and 9.71±0.05 nm, respectively. HuAITg HDL consists primarily of three distinct HDL size subpopulations with peak diameters of 10.35±0.08 nm, 8.80±0.06 nm, 7.40±0.10 nm, and HuAICETPTg HDL also consists primarily of three distinct HDL size subpopulations with peak diameters of 9.87±0.05 nm, 8.60±0.10 nm, 7.30±0.15 nm before, and 9.71±0.08 nm, 8.50±0.11 nm, 7.27±0.15 nm after zinc induction, respectively. Western blotting analysis of nondenaturing gradient gels of plasma with a monoclonal antibody to CETP indicated that in HuCETPTg and HuAICETPTg mice, 22 and 100%, respectively, of the CETP was HDL associated. Turnover studies with HDL doubly labeled with 125I apo A-I and 3H cholesteryl linoleate indicated that the CETP-induced fall in HDL-C was associated with increased HDL-cholesterol ester fractional catabolic rate in both the absence and presence of human apo A-I, suggesting CETP-mediated transfer of HDL-cholesterol ester to apo Bcontaining lipoproteins. In summary, these studies suggest that CETP has a much more profound effect on HDL cholesterol levels in transgenic animals expressing human apo A-I. This
Endogenous apolipoprotein E in VLDL is poorly expressed in receptor binding processes The ligand responsible for receptor interaction of lipolyzed VLDL (apo E or apo B-100) and its source (endogenous or transferred) was studied with monoclonal antibodies and with lipoproteins from E-3/3 and E-2/2 subjects. The data unequivocally proved that lipolysis causes exposure of unreactive endogenous apo E-3 at the VLDL surface, possibly by a change of conformation of the protein. Apo B-100 becomes biologically expressed only in lipolyzed VLDL-III. Lipolyzed VLDL, however, is less reactive to exogenous apo E-3 than control VLDL indicating that endogenous and exogenous apo E are oriented differently in VLDL. It is proposed that VLDL delivers triglycerides to tissues when apo E is unreactive but becomes a remnant after the protein becomes exposed and directs the particles from lipoprotein lipase sites to cellular receptors. (J. Clin. Invest. 1991. 88:553-560.)
Objective: To evaluate the effect of low doses of warfarin in patients with systemic sclerosis with disseminated subcutaneous calcinosis. Methods: Three patients with disseminated subcutaneous calcinosis were treated with low doses of warfarin for 1 year. Subcutaneous calcinotic lesions, coagulation blood parameters, and the tendency for bleeding were followed up during the year. Results: Two of the patients, who had newly diagnosed, diffuse, and relatively small calcinotic lesions, responded to warfarin treatment, with complete resolution of the calcinosis. The other patient, with larger and longer standing calcinotic lesions, did not respond to warfarin treatment. None of the three patients showed a prolongation of prothrombin time or partial thromboplastin time, nor did any have an increased tendency for bleeding. Conclusions: Low dose warfarin may serve as an effective treatment for calcinosis in a selected group of patients who have small and relatively new onset calcinosis. This treatment does not prolong the coagulation of blood and there is no increased tendency for bleeding. D iffuse calcinosis is a common manifestation of systemic sclerosis, mainly affecting the extremities.1 The subcutaneous calcium deposits may erode the skin and predispose these areas to secondary infection, yet no currently approved medical treatment exists. Rare anecdotal reports suggest that low dose warfarin may have a role in reducing the size of calcinotic plaques.2-4 We describe three patients who had multiple calcinotic lesions secondary to systemic sclerosis and who were treated with warfarin for 1 year, with results varying in accordance with the age and size of the calcinotic lesions. CASE REPORTSCase 1 A 35 year old female patient of Arab origin had limited cutaneous systemic sclerosis, manifested as severe Raynaud's phenomenon, oesophageal dysmotility, hidebound skin overlying both hands and face resulting in microstomia and puffy hands and pulmonary hypertension, positive antinuclear antibodies (three out of four), and negative anticentromere antibodies. Penicillamine treatment was ineffective, and the patient was treated with oral calcium channel blockers and with infusions of prostacyclin analogue.During follow up the patient was found to develop multiple painless subcutaneous calcium deposits on her knuckles and elbows, up to 2 cm in diameter. She consented to treatment with warfarin, which was started at a low dose of 1 mg/day. Within 2 months all the calcinotic lesions had completely disappeared, leaving only small areas of skin discolouration.Treatment was continued with warfarin for a year without recurrence of the calcinotic lesions. On follow up (at 2 years), no recurrence of the calcinotic lesions was seen. During treatment the prothrombin time (PT) and partial thromboplastin time (PTT) were repeatedly measured and were found to remain within normal values, with no clinically increased tendency for bleeding noted.Case 2 A 30 year old female patient of Arab origin was known to have had diffuse cutaneous system...
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