scholarly journals Hyperhomocysteinemia and Dyslipidemia in point mutation G307S of cystathionine β-synthase-deficient rabbit generated using CRISPR/Cas9

2020 ◽  
Author(s):  
Ting Zhang ◽  
Rui Lu ◽  
Yibing Chen ◽  
Yuguo Yuan ◽  
Shaozheng Song ◽  
...  
Keyword(s):  
Point Mutation ◽  
Plasma Levels ◽  
Low Density Lipoprotein ◽  
Rabbit Model ◽  
Density Lipoprotein ◽  
Causative Factor ◽  
Normal Diet ◽  
Vitamin B ◽  
Low Density Lipoprotein Cholesterol ◽  
Rabbit Embryos

Abstract Background: Congenital hyper-homocysteinemia (HHcy) is caused by a defective cystathionine β-synthase (CBS) gene, and is frequently associated with dyslipdemia. The aim of this study was to further elucidate the effect of mutated CBS gene on circulating lipids using a rabbit model harboring a homozygous G307S point mutation in CBS. Methods: CRISPR/Cas9 system was used to edit the CBS gene in rabbit embryos. The founder rabbits were sequenced, and their plasma homocysteine (Hcy) and lipid profile were analyzed. Results: Six CBS-knockout (CBS-KO) founder lines with biallelic modifications were obtained. Mutation in CBS caused significant growth retardation and high mortality rates within 6 weeks after birth. In addition, the 6-week old CBS-KO rabbits showed higher plasma levels of Hcy, triglycerides (TG), total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) compared to the age-matched wild-type (WT) controls. Histological analysis of the mutants showed accumulation of micro-vesicular cytoplasmic lipid droplets in the hepatocytes. However, gastric infusion of vitamin B and betaine complex significantly decreased the plasma levels of TG, TC and LDL-C in the CBS-KO rabbits, and alleviated hepatic steatosis compared to the untreated animals. Conclusion: A CBSG307S rabbit model was generated that exhibited severe dyslipidemia when fed on a normal diet, indicating that G307S mutation in the CBS gene is a causative factor for dyslipidemia.

scholarly journals Hyperhomocysteinemia and Dyslipidemia in point mutation G307S of cystathionine β-synthase-deficient rabbit generated using CRISPR/Cas9

2020 ◽  
Author(s):  
Ting Zhang ◽  
Rui Lu ◽  
Yibing Chen ◽  
Yuguo Yuan ◽  
Shaozheng Song ◽  
...  
Keyword(s):  
Point Mutation ◽  
Plasma Levels ◽  
Low Density Lipoprotein ◽  
Rabbit Model ◽  
Density Lipoprotein ◽  
Causative Factor ◽  
Normal Diet ◽  
Vitamin B ◽  
Low Density Lipoprotein Cholesterol ◽  
Rabbit Embryos

Abstract Background: Congenital hyper-homocysteinemia (HHcy) is caused by a defective cystathionine β-synthase (CBS) gene, and is frequently associated with dyslipdemia. The aim of this study was to further elucidate the effect of mutated CBS gene on circulating lipids using a rabbit model harboring a homozygous G307S point mutation in CBS.Methods: CRISPR/Cas9 system was used to edit the CBS gene in rabbit embryos. The founder rabbits were sequenced, and their plasma homocysteine (Hcy) and lipid profile were analyzed.Results: Six CBS-knockout (CBS-KO) founder lines with biallelic modifications were obtained. Mutation in CBS caused significant growth retardation and high mortality rates within 6 weeks after birth. In addition, the 6-week old CBS-KO rabbits showed higher plasma levels of Hcy, triglycerides (TG), total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) compared to the age-matched wild-type (WT) controls. Histological analysis of the mutants showed accumulation of micro-vesicular cytoplasmic lipid droplets in the hepatocytes. However, gastric infusion of vitamin B and betaine complex significantly decreased the plasma levels of TG, TC and LDL-C in the CBS-KO rabbits, and alleviated hepatic steatosis compared to the untreated animals.Conclusion: A CBSG307S rabbit model was generated that exhibited severe dyslipidemia when fed on a normal diet, indicating that G307S mutation in the CBS gene is a causative factor for dyslipidemia.

scholarly journals Hyperhomocysteinemia and dyslipidemia in point mutation G307S of cystathionine β-synthase-deficient rabbit generated using CRISPR/Cas9

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Ting Zhang ◽  
Rui Lu ◽  
Yibing Chen ◽  
Yuguo Yuan ◽  
Shaozheng Song ◽  
...  
Keyword(s):  
Point Mutation ◽  
Plasma Levels ◽  
Low Density Lipoprotein ◽  
Rabbit Model ◽  
Density Lipoprotein ◽  
Causative Factor ◽  
Normal Diet ◽  
Vitamin B ◽  
Low Density Lipoprotein Cholesterol ◽  
Rabbit Embryos

Abstract Background Congenital hyper-homocysteinemia (HHcy) is caused by a defective cystathionine β-synthase (CBS) gene, and is frequently associated with dyslipdemia. The aim of this study was to further elucidate the effect of mutated CBS gene on circulating lipids using a rabbit model harboring a homozygous G307S point mutation in CBS. Methods CRISPR/Cas9 system was used to edit the CBS gene in rabbit embryos. The founder rabbits were sequenced, and their plasma homocysteine (Hcy) and lipid profile were analyzed. Results Six CBS-knockout (CBS-KO) founder lines with biallelic modifications were obtained. Mutation in CBS caused significant growth retardation and high mortality rates within 6 weeks after birth. In addition, the 6-week old CBS-KO rabbits showed higher plasma levels of Hcy, triglycerides (TG), total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) compared to the age-matched wild-type (WT) controls. Histological analysis of the mutants showed accumulation of micro-vesicular cytoplasmic lipid droplets in the hepatocytes. However, gastric infusion of vitamin B and betaine complex significantly decreased the plasma levels of TG, TC and LDL-C in the CBS-KO rabbits, and alleviated hepatic steatosis compared to the untreated animals. Conclusion A CBSG307S rabbit model was generated that exhibited severe dyslipidemia when fed on a normal diet, indicating that G307S mutation in the CBS gene is a causative factor for dyslipidemia.

scholarly journals Hyperhomocysteinemia and Dyslipidemia in point mutation G307S of cystathionine β-synthase-deficient rabbit generated using CRISPR/Cas9

2020 ◽  
Author(s):  
Ting Zhang ◽  
Rui Lu ◽  
Yibing Chen ◽  
Yuguo Yuan ◽  
Shaozheng Song ◽  
...  
Keyword(s):  
Point Mutation ◽  
Plasma Levels ◽  
Lipid Droplets ◽  
Histological Analysis ◽  
Rabbit Model ◽  
Causative Factor ◽  
Normal Diet ◽  
Vitamin B ◽  
Wild Type ◽  
Rabbit Embryos

Abstract Background: Congenital hyper-homocysteinemia (HHcy) is caused by a defective cystathionine β-synthase (CBS) gene, and is frequently associated with dyslipdemia. The aim of this study was to further elucidate the effect of mutated CBS gene on circulating lipids using a rabbit model harboring a homozygous G307S point mutation in CBS.Methods: CRISPR/Cas9 system was used in rabbit embryos to edit their CBS gene. The founder rabbits were sequenced, and their plasma Hcy and lipid profile were analyzed. Results: Six CBS-KO founder lines with biallelic modifications were obtained. Mutation in CBS caused significant growth retardation and high mortality rates within 6 weeks after birth. In addition, the 6-week old CBS-KO rabbits showed higher plasma levels of Hcy, TG, TC and LDL-C compared to the age-matched wild-type (WT) controls. Histological analysis of the mutants showed accumulation of micro-vesicular cytoplasmic lipid droplets in the hepatocytes. However, gastric infusion of vitamin B and betaine complex significantly decreased the plasma levels of TG, TC and LDL-C in the CBS-KO rabbits, as well as hepatic steatosis compared to the untreated animals. Conclusion: We generated CBSG307S rabbit model that exhibited severe dyslipidemia when fed on a normal diet, indicating that G307S mutation in the CBS gene is a causative factor for dyslipidemia.

scholarly journals A Spectrum of PCSK9 Alleles Contributes to Plasma Levels of Low-Density Lipoprotein Cholesterol

2006 ◽  
Vol 78 (3) ◽  
pp. 410-422 ◽  
Author(s):  
Ingrid K. Kotowski ◽  
Alexander Pertsemlidis ◽  
Amy Luke ◽  
Richard S. Cooper ◽  
Gloria L. Vega ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Low Density ◽  
Low Density Lipoprotein Cholesterol

scholarly journals Why Should We Measure Low-Density Lipoprotein Cholesterol Directly? Comparison of Low-Density Lipoprotein Cholesterol Assessment by Friedewald Estimation, and Direct Measurement

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A305-A305
Author(s):  
Hofit Cohen
Keyword(s):  
Direct Measurement ◽  
Plasma Levels ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Low Density ◽  
Low Density Lipoprotein Cholesterol ◽  
Wide Range ◽  
Friedewald Equation ◽  
The Difference

Abstract Intorduction: Plasma levels of low-density lipoprotein cholesterol (LDL-C) are an important biomarker for coronary artery disease. In clinical and research settings worldwide, levels LDL-C are often not measured and are estimated using the Friedewald equation (total cholesterol - HDL cholesterol - triglycerides)/5). Bias of either over or underestimation of LDL-C can be corrected by direct measurement of LDL-C. We assessed the precision of the Friedewald equation in a heterogonous patients population within a wide range of lipid levels. Methods: A sample of consecutive fasting lipid profiles was obtained from ambulatory and hospitalized patients at the Chaim Sheba Medical Center, Tel-Hashomer. LDL-C concentrations were directly measured (dir LDL-C) (Olympus, Ireland) and correspondingly calculated at by the Friedewald equation (calc LDL-C). Results: 32,245 samples were analyzed. In 93% of the samples, underestimation of plasma levels of LDL-C was observed using the Friedewald equation. In 11,054 patients (34.3%), the difference between dir LDL and calc LDL were over 10mg/dl. In 7,693 patients (23.8%), the difference between dir LDL and calc LDL were over 20mg/dl. The difference between dir LDL and calc LDL correlated with plasma TG levels, including TG levels within the normal range. The difference between cal LDL and dir LDL levels is inversely correlated to cholesterol plasma levels. Conclusions: Direct measurement of LDL-C is more precise than Friedewald’s formula and overcomes the inaccurateness, due to elevated TG levels or relatively low LDL-C levels, in the setting of a heterogeneous Israeli population. In the era of extremely low LDL-C treatment goals, our findings require consideration due to their clinical importance and direct measurement of plasma LDL-C should be implemented as underestimation of LDL levels may lead to inappropriate therapeutic decisions.

scholarly journals Hypolipidemic Activity of Tetracarpidium conophorum (African walnut) Seed Oil and Its Mechanism of Action

2020 ◽  
Vol 07 (04) ◽  
pp. e170-e178
Author(s):  
Kelly Oriakhi ◽  
Patrick Uadia
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Normal Diet ◽  
Lipoprotein Cholesterol ◽  
High Cholesterol Diet ◽  
Low Density ◽  
Low Density Lipoprotein Cholesterol ◽  
Protein Levels ◽  
Reactive Protein ◽  
Aspartate Amino Transferase

AbstractThe present study was designed to evaluate the hypolipidemic activity of Tetracarpidium conophorum oil and its mechanism(s) of action. The oil was extracted using the Soxhlet method and subjected to column chromatography/spectroscopic techniques. GC-MS analysis was performed on the oil to identify 15 constituents with 9,12,15-octadecatrienoic acid (ω-3 fatty acid or α-linolenic acid) (68%) showing the highest proportion. Isolation and purification of the oil gave three compounds, namely, β-sitosterol, stigmasterol, and stearic acid (octadecanoic acid). Thirty-five rats were used and divided into seven groups for the in vivo hypolipidemic study. Findings from this study showed significant decreases (p<0.05) in total cholesterol, triglycerides, and low-density lipoprotein cholesterol, and an increase in high-density lipoprotein cholesterol in rats fed a normal diet and receiving T. conophorum oil (250 and 500 mg/kg body weight) for 20 days. But there were significant increases (p<0.05) in total cholesterol, triglycerides, low-density lipoprotein cholesterol, creatine kinase, lactate dehydrogenase, aspartate amino transferase, malondialdehyde, 3-hydroxy-3-methylglutaryl-coenzyme A reductase, and C-reactive protein levels with a decline in the low-density lipoprotein cholesterol level in rats fed the high cholesterol diet when compared to those fed a normal diet. However, oral administration of T. conophorum oil and atorvastatin for 20 days resulted in a significant lowering (p<0.05) of triglycerides, low-density lipoprotein cholesterol, creatine kinase, lactate dehydrogenase, aspartate amino transferase, malondialdehyde, 3-hydroxy-3-methylglutaryl-coenzyme A reductase, and C-reactive protein levels with a rise in high-density lipoprotein cholesterol in rats nourished with the high cholesterol diet. The study showed that T. conophorum seed oil possesses hypolipidemic and cardioprotective properties.

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