Hyperlipidemia induces typical atherosclerosis development in Ldlr and Apoe deficient rats

Zhao, Yongliang; Yang, Yi‐Qing; Xing, Roumei; Cui, Xueqin; Xiao, Yufang; Xie, Ling; You, Panpan; Wang, Tongtong; Zeng, Li; Peng, Wenhui; Li, Dali; Chen, Huaqing; Liu, Mingyao

doi:10.1016/j.atherosclerosis.2018.02.015

Cited by 84 publications

(75 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Hyperlipidaemia is an important atherogenic factor by promoting the formation and accumulation of lipid plaques in the arteries. 1,2 Currently, statins are the leading lipid-lowering drugs that inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme for de novo synthesis of cholesterol. 3 However, increasing numbers of studies have reported side effects of statins.…”

Section: Introductionmentioning

confidence: 99%

The marine‐derived furanone reduces intracellular lipid accumulation in vitro by targeting LXRα and PPARα

Pang

et al. 2020

J Cellular Molecular Medi

View full text Add to dashboard Cite

Recent studies have demonstrated that commercially available lipid‐lowering drugs cause various side effects; therefore, searching for anti‐hyperlipidaemic compounds with lower toxicity is a research hotspot. This study was designed to investigate whether the marine‐derived compound, 5‐hydroxy‐3‐methoxy‐5‐methyl‐4‐butylfuran‐2(5H)‐one, has an anti‐hyperlipidaemic activity, and the potential underlying mechanism in vitro. Results showed that the furanone had weaker cytotoxicity compared to positive control drugs. In RAW 264.7 cells, the furanone significantly lowered ox‐LDL‐induced lipid accumulation (~50%), and its triglyceride (TG)‐lowering effect was greater than that of liver X receptor (LXR) agonist T0901317. In addition, it significantly elevated the protein levels of peroxisome proliferator‐activated receptors (PPARα) and ATP‐binding cassette (ABC) transporters, which could be partially inhibited by LXR antagonists, GSK2033 and SR9243. In HepG2 cells, it significantly decreased oleic acid‐induced lipid accumulation, enhanced the protein levels of low‐density lipoprotein receptor (LDLR), ABCG5, ABCG8 and PPARα, and reduced the expression of sterol regulatory element‐binding protein 2 (~32%). PPARα antagonists, GW6471 and MK886, could significantly inhibit the furanone‐induced lipid‐lowering effect. Furthermore, the furanone showed a significantly lower activity on the activation of the expression of lipogenic genes compared to T0901317. Taken together, the furanone exhibited a weak cytotoxicity but had powerful TC‐ and TG‐lowering effects most likely through targeting LXRα and PPARα, respectively. These findings indicate that the furanone has a potential application for the treatment of dyslipidaemia.

show abstract

Section: Introductionmentioning

confidence: 99%

The marine‐derived furanone reduces intracellular lipid accumulation in vitro by targeting LXRα and PPARα

Pang

et al. 2020

J Cellular Molecular Medi

View full text Add to dashboard Cite

show abstract

“…This study shows that targeting APOE in various CNS cell types can lead to beneficial functional alterations in patient-derived in vitro systems. In animal models, CRISPR/Cas9 is relatively safe and has been successfully used to generate APOE KO in pigs and rats with little to no off-target incidents or mosaicism [159][160][161]. However, there is always the possibility of unexpected edits in the targeted and non-targeted portions of the genome leading to unanticipated side effects as well as triggering cancer risk [162,163].…”

Section: Crispr/cas9 Mediated Gene Editingmentioning

confidence: 99%

Therapeutic approaches targeting Apolipoprotein E function in Alzheimer’s disease

Williams

Borchelt

Chakrabarty

2020

Mol Neurodegeneration

118

View full text Add to dashboard Cite

One of the primary genetic risk factors for Alzheimer's disease (AD) is the presence of the Ɛ4 allele of apolipoprotein E (APOE). APOE is a polymorphic lipoprotein that is a major cholesterol carrier in the brain. It is also involved in various cellular functions such as neuronal signaling, neuroinflammation and glucose metabolism. Humans predominantly possess three different allelic variants of APOE, termed E2, E3, and E4, with the E3 allele being the most common. The presence of the E4 allele is associated with increased risk of AD whereas E2 reduces the risk. To understand the molecular mechanisms that underlie APOE-related genetic risk, considerable effort has been devoted towards developing cellular and animal models. Data from these models indicate that APOE4 exacerbates amyloid β plaque burden in a dose-dependent manner. and may also enhance tau pathogenesis in an isoform-dependent manner. Other studies have suggested APOE4 increases the risk of AD by mechanisms that are distinct from modulation of Aβ or tau pathology. Further, whether plasma APOE, by influencing systemic metabolic pathways, can also possibly alter CNS function indirectly is not complete;y understood. Collectively, the available studies suggest that APOE may impact multiple signaling pathways and thus investigators have sought therapeutics that would disrupt pathological functions of APOE while preserving or enhancing beneficial functions. This review will highlight some of the therapeutic strategies that are currently being pursued to target APOE4 towards preventing or treating AD and we will discuss additional strategies that holds promise for the future.

show abstract

“…Fatty liver phenotypes similar to those observed in Ldlr-edited mice were also found in rats upon CRISPR/Cas9-mediated deletion of apolipoprotein E (Apoe). 73 ApoE is a component of lipoprotein remnants; its deficiency in humans leads to decreased clearance of remnants and an increased risk of atherosclerosis, a condition known as familial dysbetalipoproteinemia. 74 CRISPR/Cas9mediated deletion of Ldlr and Apoe (either individually or in combination) was achieved by zygote microinjection of sgRNA and Cas9 mRNA, generating adult rats that exhibit hypercholesterolemia, hepatic steatosis, and atherosclerosis.…”

Section: Familial Hypercholesterolemiamentioning

confidence: 99%

“…74 CRISPR/Cas9mediated deletion of Ldlr and Apoe (either individually or in combination) was achieved by zygote microinjection of sgRNA and Cas9 mRNA, generating adult rats that exhibit hypercholesterolemia, hepatic steatosis, and atherosclerosis. 73 Primary hyperoxaluria type I disease Recently, Zheng et al generated a rat model of primary hyperoxaluria type I disease. 75 The authors deleted alanine-glyoxylate aminotransferase in rat zygotes, resulting in severe nephrocalcinosis due to the formation of oxalate crystals, as seen in humans.…”

Section: Familial Hypercholesterolemiamentioning

confidence: 99%

Using CRISPR/Cas9 to model human liver disease

et al. 2019

View full text Add to dashboard Cite

CRISPR/Cas9 gene editing has revolutionised biomedical research. The ease of design has allowed many groups to apply this technology for disease modelling in animals. While the mouse remains the most commonly used organism for embryonic editing, CRISPR is now increasingly performed with high efficiency in other species. The liver is also amenable to somatic genome editing, and some delivery methods already allow for efficient editing in the whole liver. In this review, we describe CRISPR-edited animals developed for modelling a broad range of human liver disorders, such as acquired and inherited hepatic metabolic diseases and liver cancers. CRISPR has greatly expanded the repertoire of animal models available for the study of human liver disease, advancing our understanding of their pathophysiology and providing new opportunities to develop novel therapeutic approaches.

show abstract

Hyperlipidemia induces typical atherosclerosis development in Ldlr and Apoe deficient rats

Cited by 84 publications

References 36 publications

The marine‐derived furanone reduces intracellular lipid accumulation in vitro by targeting LXRα and PPARα

The marine‐derived furanone reduces intracellular lipid accumulation in vitro by targeting LXRα and PPARα

Therapeutic approaches targeting Apolipoprotein E function in Alzheimer’s disease

Using CRISPR/Cas9 to model human liver disease

Contact Info

Product

Resources

About