scholarly journals A novel peroxisome proliferator response element modulates hepatic low-density lipoprotein receptor gene transcription in response to PPARδ activation

2015 ◽  
Vol 472 (3) ◽  
pp. 275-286 ◽  
Author(s):  
Vikram R. Shende ◽  
Amar Bahadur Singh ◽  
Jingwen Liu
Keyword(s):  
Gene Transcription ◽  
Receptor Gene ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Peroxisome Proliferator ◽  
Density Lipoprotein Receptor ◽  
Peroxisome Proliferator Response Element

PPARδ activation beneficially regulates lipid metabolism. We have now identified a novel function of PPARδ that increases LDL receptor gene transcription in hepatic cells in vitro and in vivo through direct binding to a PPRE motif on LDLR promoter.

scholarly journals Low-Density Lipoprotein Receptor-Mediated Lipidome-Transcriptome Reprogramming Impulses to Cisplatin Insensitivity

2018 ◽  
Author(s):  
Wei-Chun Chang ◽  
Hsiao-Ching Wang ◽  
Wei-Chung Cheng ◽  
Juan-Cheng Yang ◽  
Wei-Min Chung ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Lipoprotein Receptor ◽  
Low Density Lipoprotein Receptor ◽  
Bioinformatics Analyses ◽  
Density Lipoprotein Receptor ◽  
Cisplatin Sensitivity

Platinum-based therapy remains the cornerstone for cancer patient management; however, its efficacy varies. This study demonstrated the differential expressions of low-density lipoprotein receptor (LDLR) in subtypes of epithelial ovarian carcinoma (EOC) determines cisplatin sensitivity. It's sensitive in serous EOCs (low LDLR), where insensitive in endometrioid and clear cell EOCs (high LDLR). Meanwhile, knocked-down or overexpressed LDLR in EOC could reversed the chemosensitivity pattern both in vitro and in vivo. Mechanistic dissection with transcriptome vs. lipidome trans-omics analyses elucidated the LDLR-->LPC (Lyso-PhosphotidylCholine)-->FAM83B (phospholipase-related)-->FGFRs (cisplatin sensitivity and phospholipase-related) regulatory axis in cisplatin insensitivity. Implementing LPC-liposome encapsulated cisplatin could facilitate DNA-adduct formation via lipid droplets (LDs) delivery. Furthermore, Bioinformatics analyses found that the LDL/R-->LD homeostasis alteration is critical for therapeutic prognosis. Lastly, using LPC-liposome-cisplatin improved cisplatin sensitivities in gastric cancer, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, and pancreatic adenocarcinoma cells. In conclusion, this report discovered a LDL/R-reprogrammed transcriptome-lipidome network, by which impulses platinum insensitivity and disease outcome. The drug specific lipidome for liposome manufacture might be an efficienct pharmaceutics strategy for chemoagents.

Abstract 908: In Vivo Role of the Pharmacogenetics of Glucuronidation in the Disposition and Triglyceride Response to Fenofibrate

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Robert J Straka ◽  
Na Li ◽  
Chantal Guillemette ◽  
Michael Y Tsai ◽  
Naomi Q Hanson ◽  
...  
Keyword(s):  
Steady State ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipid Lowering ◽  
Peroxisome Proliferator ◽  
Fenofibric Acid ◽  
Lipid Response ◽  
Study Participants

In spite of optimal low-density lipoprotein (LDL-C) lowering with statins, cardiovascular risk remains high for patients with elevated triglyceride (TG)-low high-density cholesterol (HDL-C) profiles. Fenofibric acid, the active moiety of fenofibrate, acts on the peroxisome proliferator-activated nuclear receptor-alpha (PPAR-α) to lower TG and raise HDL-C. The extent of lipid response has been shown to be associated with serum concentrations (conc.) of fenofibric acid. In vitro work confirms fenofibric acid is primarily eliminated by UDP-glucuronosyltransferases (UGTs) including UGT2B7, and others (UGT1A1, UGT1A3 and UGT1A9). Therefore, we hypothesized genetic variations in UGT activity may be associated with fenofibric acid conc. and thus may influence lipid response. Purpose: To test if the A-327G SNP (rs7662029) for UGT2B7, which has been shown to modulate UGT2B7 expression in vitro, is associated with serum conc. of fenofibric acid and TG response in vivo . Methods: As part of the NHLBI sponsored Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study, participants providing consent and not currently taking lipid lowering medications, were analyzed for fasting lipid response pre and post 21 days of once daily 160mg fenofibrate. TG response was calculated by the log of the ratio of the average of the 2 pre- and post-fenofibrate exposure TG determinations. Associations between UGT2B7 A-327G genotype and steady-state trough fenofibric acid conc. as well as TG response were analyzed by linear regression. Results : 745 participants (51% male) with both genotype and phenotype data were included. The mean (SD) age was 49 (16) years and the median (25 th ,75 th percentile) % change in TG concentrations was -32.3 (−45.2, −19.0). The G allele frequency for UGT2B7A>G was 0.49 and was in HWE (p = 0.8). After adjusting for age, age 2 , sex, alcohol use, height and serum creatinine, strong associations were observed between UGT2B7 A-327G genotypes and steady-state trough fenofibric acid conc. (log-transformed, p = 4 × 10 −8 ) as well as TG response (p = 0.002, also adjusted for baseline TG). Conclusion : This study suggests UGT2B7 A-327G genotype may contribute to TG response by way of influencing glucuronidation activity of fenofibric acid.

scholarly journals Low-density lipoprotein receptor (LDLR) regulates NLRP3-mediated neuronal pyroptosis following cerebral ischemia/reperfusion injury

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Rui Sun ◽  
Mengna Peng ◽  
Pengfei Xu ◽  
Feihong Huang ◽  
Yi Xie ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Ischemia Reperfusion ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Neurological Deficits ◽  
Density Lipoprotein Receptor ◽  
Cerebral Ischemic

Abstract Background Inflammatory response has been recognized as a pivotal pathophysiological process during cerebral ischemic stroke. NLRP3 inflammasome, involved in the regulation of inflammatory cascade, can simultaneously lead to GSDMD-executed pyroptosis in cerebral ischemia. Low-density lipoprotein receptor (LDLR), responsible for cholesterol uptake, was noted to exert potential anti-inflammatory bioactivities. Nevertheless, the role of LDLR in neuroinflammation mobilized by cerebral ischemia/reperfusion (I/R) has not been investigated. Methods Ischemic stroke mice model was accomplished by middle cerebral artery occlusion. Oxygen-glucose deprivation was employed after primary cortical neuron was extracted and cultured. A pharmacological inhibitor of NLRP3 (CY-09) was administered to suppress NLPR3 activation. Histological and biochemical analysis were performed to assess the neuronal death both in vitro and in vivo. In addition, neurological deficits and behavioral deterioration were evaluated in mice. Results The expression of LDLR was downregulated following cerebral I/R injury. Genetic knockout of Ldlr enhanced caspase-1-dependent cleavage of GSDMD and resulted in severe neuronal pyroptosis. LDLR deficiency contributed to excessive NLRP3-mediated maturation and release of IL-1β and IL-18 under in vitro and in vivo ischemic conditions. These influences ultimately led to aggravated neurological deficits and long-term cognitive dysfunction. Blockade of NLRP3 substantially retarded neuronal pyroptosis in Ldlr−/− mice and cultured Ldlr−/− neuron after experimental stroke. Conclusions These results demonstrated that LDLR modulates NLRP3-mediated neuronal pyroptosis and neuroinflammation following ischemic stroke. Our findings characterize a novel role for LDLR as a potential therapeutic target in neuroinflammatory responses to acute cerebral ischemic injury.

scholarly journals Deletion of two growth-factor repeats from the low-density-lipoprotein receptor accelerates its degradation

1991 ◽  
Vol 277 (3) ◽  
pp. 677-682 ◽  
Author(s):  
D R van der Westhuyzen ◽  
M L Stein ◽  
H E Henderson ◽  
A D Marais ◽  
A M Fourie ◽  
...  
Keyword(s):  
Growth Factor ◽  
Sequence Similarity ◽  
Receptor Gene ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Low Density ◽  
Density Lipoprotein Receptor ◽  
Epidermal Growth ◽  
Mutant Receptors

The region of the low-density-lipoprotein (LDL) receptor showing sequence similarity to the epidermal-growth-factor (EGF) precursor is required for LDL binding and the acid-induced dissociation of ligand and receptor. We describe here a naturally occurring mutant LDL receptor, found in a patient with homozygous familial hypercholesterolaemia, which lacks the first two growth-factor-like repeats of the EGF-precursor-like (‘homology’) domain. The mutation in the receptor gene is a 2.5 kb deletion including exons 7 and 8. The molecular mass of the mutant receptor (145 kDa) was approx. 15 kDa smaller than the normal LDL receptor. The mutant receptors were derived from precursors (105 kDa) that apparently underwent normal processing. Fibroblasts from the patient had high-affinity binding sites for the the apolipoprotein E-containing ligand, beta VLDL, but did not bind LDL. In the presence of beta VLDL, receptors were rapidly degraded. The mutant receptors also displayed an abnormally rapid turnover, about four times faster than that of normal receptors, in the absence of ligand; this accelerated degradation accounted for the low level of expression of mutant receptors in up-regulated cells. These data support a role for the growth-factor-like repeats in the binding of LDL (but not beta VLDL) and in receptor recycling, and indicate that a normal rate of turnover of unoccupied receptors is dependent on the integrity of these segments of the protein.

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