A Vaccine Targeted at CETP Alleviates High Fat and High Cholesterol Diet-Induced Atherosclerosis and Non-Alcoholic Steatohepatitis in Rabbit

Liaw, Yi Wei; Lin, Chia‐Hua; Lai, Yu‐Sheng; Yang, Tzu Chung; Wang, Chau Jong; Whang‐Peng, Jacqueline; Liu, Leroy F.; Lin, Chia Po; Nieh, Shin; Lu, Shao Chun; Hwang, Jaulang

doi:10.1371/journal.pone.0111529

Cited by 29 publications

(9 citation statements)

References 44 publications

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“…Furthermore, recent studies demonstrated that circulating cholesteryl ester transfer protein (CETP) derives largely from hepatic Kupffer cells, and its levels parallel the severity of histological necroinflammations in NASH (111). Of note, CETP inhibitors alleviate high-fat diet-induced steatohepatitis and fibrosis, possibly by reducing oxidized LDL uptake by hepatic Kupffer and stellate cells (112), and represent a potential therapeutic target for the treatment of both NAFLD and CKD (Table 2).…”

Section: Nafld As a Determinant Of Ckd: Targeting The Liver To Improvmentioning

confidence: 99%

Fatty Liver and Chronic Kidney Disease: Novel Mechanistic Insights and Therapeutic Opportunities

et al. 2016

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Chronic kidney disease (CKD) is a risk factor for end-stage renal disease (ESRD) and cardiovascular disease (CVD). ESRD or CVD develop in a substantial proportion of patients with CKD receiving standard-of-care therapy, and mortality in CKD remains unchanged. These data suggest that key pathogenetic mechanisms underlying CKD progression go unaffected by current treatments. Growing evidence suggests that nonalcoholic fatty liver disease (NAFLD) and CKD share common pathogenetic mechanisms and potential therapeutic targets. Common nutritional conditions predisposing to both NAFLD and CKD include excessive fructose intake and vitamin D deficiency. Modulation of nuclear transcription factors regulating key pathways of lipid metabolism, inflammation, and fibrosis, including peroxisome proliferatoractivated receptors and farnesoid X receptor, is advancing to stage III clinical development. The relevance of epigenetic regulation in the pathogenesis of NAFLD and CKD is also emerging, and modulation of microRNA21 is a promising therapeutic target. Although single antioxidant supplementation has yielded variable results, modulation of key effectors of redox regulation and molecular sensors of intracellular energy, nutrient, or oxygen status show promising preclinical results. Other emerging therapeutic approaches target key mediators of inflammation, such as chemokines; fibrogenesis, such as galectin-3; or gut dysfunction through gut microbiota manipulation and incretin-based therapies. Furthermore, NAFLD per se affects CKD through lipoprotein metabolism and hepatokine secretion, and conversely, targeting the renal tubule by sodium-glucose cotransporter 2 inhibitors can improve both CKD and NAFLD. Implications for the treatment of NAFLD and CKD are discussed in light of this new therapeutic armamentarium. EPIDEMIOLOGICAL EVIDENCE LINKING NAFLD AND CKDChronic kidney disease (CKD) affects up to 8% of the world's adult population, with its prevalence increasing in an aging population beset by lifestyle-associated diseases such as obesity, the metabolic syndrome, diabetes, hypertension, and smoking (1). CKD may progress to end-stage renal disease (ESRD) and is an important cardiovascular disease (CVD) risk factor. Importantly, most patients with CKD die as a result of CVD before renal replacement therapy is initiated (1).There is potential for improving recognition and treatment of CKD. In the Third National Health and Nutrition Survey, awareness among patients with stage 3 CKD was ,8% (1). Furthermore, ESRD or CVD develop in a substantial proportion of patients with CKD receiving standard-of-care therapy, and all-cause mortality remains unchanged in the CKD population (2). These data suggest that key pathogenetic mechanisms underlying

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Section: Nafld As a Determinant Of Ckd: Targeting The Liver To Improvmentioning

confidence: 99%

Fatty Liver and Chronic Kidney Disease: Novel Mechanistic Insights and Therapeutic Opportunities

et al. 2016

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“…Feeding cholesterol to rabbits is a widely used model for experimental atherosclerosis studies [24, 25]. We reported that an atherogenic diet induced inflammation in aortic atherosclerotic plaque and elevation of plasma ox-LDL, detected using an ox-LDL enzyme-linked immunosorbent assay (ELISA) kit, in rabbits [26]. In the present study, we isolated native LDL (nLDL) and LDL(-) from the plasma of rabbits fed an atherogenic diet.…”

Section: Introductionmentioning

confidence: 99%

Electronegative LDL from Rabbits Fed with Atherogenic Diet Is Highly Proinflammatory

Chang

Pai

Lai

et al. 2019

Mediators of Inflammation

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Electronegative low-density lipoprotein (LDL(-)) has been found in the plasma of familial hypercholesterolemia and acute myocardial infarction and has been implicated in atherosclerosis and cardiovascular disease. However, less is known about the involvement of LDL(-) in atherosclerosis-related inflammation. This study aims at investigating the inducibility of LDL(-) by atherogenic diet in rabbits and at exploring the proinflammatory potential of the diet-induced LDL(-) in macrophages. Rabbits were fed with an atherogenic diet; LDL was isolated from plasma by NaBr density gradient ultracentrifugation and was then resolved into nLDL and LDL(-) by anion-exchange chromatography. Isolated nLDL and LDL(-) were directly used or incubated with 10 μM CuSO4 for 24 h to produce copper- (Cu-) ox-nLDL and Cu-ox-LDL(-). The effects of these LDLs on inflammation were evaluated in THP-1-derived macrophages. Macrophages were treated with nLDL, LDL(-), and extensively oxidized LDL (ox-LDL), then the levels of interleukin- (IL-) 1β, IL-6, and tumor necrosis factor- (TNF-) α in a culture medium were determined by ELISA, and the levels of total and phosphorylated IκB, p65, p38, JNK, and ERK in cell lysates were determined by Western blotting. The LDL(-) induced significantly higher levels of IL-1β, IL-6, and TNF-α in the medium. The levels of phosphorylated/total IκB, p65, p38, JNK, and ERK were also upregulated by LDL(-). In contrast, nLDL, Cu-ox-nLDL, and Cu-ox-LDL(-) exhibited much less effect. Knockdown of lectin-type oxidized LDL receptor- (LOX-) 1 resulted in significant reduction in LDL(-)-induced IL-1β, IL-6, and TNF-α. In addition, these LDL(-) effects were also markedly attenuated by inhibition of NF-κB and ERK1/2. The data suggested that LDL(-) induced inflammation through LOX-1-, NF-κB-, and ERK1/2-dependent pathways. Taken together, our results show that rabbits fed with atherogenic diet produce a highly proinflammatory LDL(-) that is more potent in inducing inflammation than nLDL and extensively oxidize LDL in macrophages. The results thus provide a novel link between diet-induced hypercholesterolemia and inflammation.

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“…The technique is also known as bactofection, in which the live bacteria are directly used to transfer the DNA to the target cells, tissues, or organs [ 18 ]. Bactofection has been widely used in the field of drug development research [ 19 ], such as cancer treatment [ 20 ], infections [ 21 ], inflammation diseases and other metabolic diseases [ 22 , 23 ]. As a DNA vaccine carrier, both native [ 24 ] or recombinant bacteria can be used.…”

Section: Introductionmentioning

confidence: 99%

Live Bacterial Vectors—A Promising DNA Vaccine Delivery System

Yurina

2018

Medical Sciences

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Vaccination is one of the most successful immunology applications that has considerably improved human health. The DNA vaccine is a new vaccine being developed since the early 1990s. Although the DNA vaccine is promising, no human DNA vaccine has been approved to date. The main problem facing DNA vaccine efficacy is the lack of a DNA vaccine delivery system. Several studies explored this limitation. One of the best DNA vaccine delivery systems uses a live bacterial vector as the carrier. The live bacterial vector induces a robust immune response due to its natural characteristics that are recognized by the immune system. Moreover, the route of administration used by the live bacterial vector is through the mucosal route that beneficially induces both mucosal and systemic immune responses. The mucosal route is not invasive, making the vaccine easy to administer, increasing the patient’s acceptance. Lactic acid bacterium is one of the most promising bacteria used as a live bacterial vector. However, some other attenuated pathogenic bacteria, such as Salmonella spp. and Shigella spp., have been used as DNA vaccine carriers. Numerous studies showed that live bacterial vectors are a promising candidate to deliver DNA vaccines.

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A Vaccine Targeted at CETP Alleviates High Fat and High Cholesterol Diet-Induced Atherosclerosis and Non-Alcoholic Steatohepatitis in Rabbit

Cited by 29 publications

References 44 publications

Fatty Liver and Chronic Kidney Disease: Novel Mechanistic Insights and Therapeutic Opportunities

Fatty Liver and Chronic Kidney Disease: Novel Mechanistic Insights and Therapeutic Opportunities

Electronegative LDL from Rabbits Fed with Atherogenic Diet Is Highly Proinflammatory

Live Bacterial Vectors—A Promising DNA Vaccine Delivery System

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