Identification of human low‐density lipoprotein receptor as a novel target gene regulated by liver X receptor alpha

Ishimoto, Kenji; Tachibana, Keisuke; Sumitomo, Mikako; Omote, Shiho; Hanano, Ikuko; Yamasaki, Daisuke; Watanabe, Yuichiro; Tanaka, Toshiya; Hamakubo, Takao; Sakai, Juro; Kodama, Tatsuhiko; Doi, Takefumi

doi:10.1016/j.febslet.2006.08.010

Cited by 39 publications

(38 citation statements)

References 18 publications

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“…Here we showed that the LXR agonist TO901317 is an activator of PCSK9 in human cells. As published recently, it also induced LDLr transcription (49). Interestingly, we found an additive effect of both drugs on LDLr regulation.…”

Section: Discussionsupporting

confidence: 69%

Dual Mechanisms for the Fibrate-mediated Repression of Proprotein Convertase Subtilisin/Kexin Type 9

Kourimate

May

Langhi

et al. 2008

Journal of Biological Chemistry

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Proprotein convertase subtilisin/kexin type 9 (PCSK9) is associated with familial autosomal dominant hypercholesterolemia and is a natural inhibitor of the LDL receptor (LDLr). PCSK9 is degraded by other proprotein convertases: PC5/6A and furin. Both PCSK9 and the LDLr are up-regulated by the hypocholesterolemic statins. Thus, inhibitors or repressors of PCSK9 should amplify their beneficial effects. In the present study, we showed that PPAR␣ activation counteracts PCSK9 induction by statins by repressing PCSK9 promoter activity and by increasing PC5/6A and furin expression. Quantification of mRNA and protein levels showed that various fibrates decreased PCSK9 and increased PC5/6A and furin expression. Fenofibric acid (FA) reduced PCSK9 protein content in immortalized human hepatocytes (IHH) as well as its cellular secretion. FA suppressed PCSK9 induction by statins or by the liver X receptor agonist TO901317. PCSK9 repression is occurring at the promoter level. We showed that PC5/6A and furin fibrate-mediated up-regulation is PPAR␣-dependent. As a functional test, we observed that FA increased by 30% the effect of pravastatin on the LDLr activity in vitro. In conclusion, fibrates simultaneously decreased PCSK9 expression while increasing PC5/6A and furin expression, indicating a broad action of PPAR␣ activation in proprotein convertase-mediated lipid homeostasis. Moreover, this study validates the functional relevance of a combined therapy associating PCSK9 repressors and statins.Proprotein convertase subtilisin/kexin type 9 (PCSK9) 3 is associated with autosomal dominant hypercholesterolemia (1) and is a natural inhibitor of the LDL receptor (LDLr) (2). Its autocatalytic activity is necessary to its processing and for the mature form to reach the LDLr and induce its degradation (3). This catalytic activity is not involved in LDLr degradation per se. Indeed, cellular or secreted mature PCSK9 probably acts as a chaperone and prevents the LDLr from being recycled by binding to its EGFA domain (4 -10). Accordingly, hepatic transient overexpression of wild-type PCSK9 in mice (11)(12)(13)(14) or elevated circulating levels in parabiotic mice (15) decrease the LDLr expression and lead to hypercholesterolemia. It has been shown that the proprotein convertase furin and to a lesser extent PC5/6A cleave PCSK9 into a secreted, truncated, inactive form (16). Interestingly, some "gain of function" mutations do not necessarily induce a higher affinity of PCSK9 for the LDLr, but decrease PCSK9 sensitivity to this degradation (4). In contrast, PCSK9 deficiency lowers plasmatic cholesterol concentration and confers protection against cardiovascular disease (17-20). Thus, treatments inhibiting PCSK9 synthesis, processing, or binding to the LDLr could be useful for hypercholesterolemic patients who do not reach therapeutic goals. In particular, these inhibitors could be added to statins to amplify their effect on the LDLr activity. Surprisingly, statins also increase PCSK9 expression via SREBP-2, a pathway that exerts a break on ...

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Section: Discussionsupporting

confidence: 69%

Dual Mechanisms for the Fibrate-mediated Repression of Proprotein Convertase Subtilisin/Kexin Type 9

Kourimate

May

Langhi

et al. 2008

Journal of Biological Chemistry

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“…The mature human SREBP-1c expression vector (pcDNA3-nSREBP1c, amino acids 1-436) was created by cloning the appropriate cDNA from HepG2-tet-off-hLXR␣ cells into the pcDNA3 vector (21). The murine NF-YA29-expressing plasmid (pcDNA3-NF-YA29) has been described previously (22).…”

Section: Methodsmentioning

confidence: 99%

Sterol-mediated Regulation of Human Lipin 1 Gene Expression in Hepatoblastoma Cells

Ishimoto

Nakamura

Tachibana

et al. 2009

Journal of Biological Chemistry

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Lipin 1 plays a crucial role in lipid metabolism in adipose tissue, skeletal muscle, and liver. Its physiological role involves two cellular functions: regulation of phosphatidate phosphatase activity and regulation of fatty acid oxidation. In this study, we have demonstrated that lipin 1 gene (LPIN1) expression is regulated by cellular sterols, which are key regulators of lipid metabolism. We have also characterized the sterol-response element and nuclear factor Y-binding sites in the human LPIN1 promoter. Using a luciferase assay, electrophoretic mobility shift assay, and chromatin immunoprecipitation assay, we demonstrated that these elements are responsible for the transcription of LPIN1 gene, mediated by SREBP-1 (sterol regulatory element-binding protein 1) and nuclear factor Y. Furthermore, we investigated whether lipin 1 is involved in lipogenesis by transfection of LPIN1 small interfering RNA. We infer that sterolmediated regulation of lipin 1 gene transcription modulates triglyceride accumulation. This modulation involves changes in the activity of phosphatidate phosphatase.

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“…The membrane-bound FATPs, FABPpm and CD36, and intracellular FABPs have so far been believed to be the lipid uptake from lipoproteins is well documented ( 45,46 ), but little information is available regarding their role in cellular fatty acid activation and fatty acid uptake per se. This article demonstrates that activation of LXR increases acyl-CoA synthetase activity through transcriptional activation of ACSL3 expression.…”

Section: Lxr Agonist Increases Fatty Acid Uptake In Bewo Cellsmentioning

confidence: 99%

Activation of LXR increases acyl-CoA synthetase activity through direct regulation of ACSL3 in human placental trophoblast cells

Weedon-Fekjær

Dalen

Solaas

et al. 2010

Journal of Lipid Research

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This article is available online at http://www.jlr.org thetases (ACSL), the fatty acid transport proteins (FATP), and the acyl-CoA synthetase bubblegum (ACSBG) family ( 1-5 ). Five genes in the ACSL family have been identifi ed based on sequence homology. They are named ACSL1 and ACSL3 to ACSL6 and differ in their tissue and intracellular distribution. The distinct intracellular location of acyl-CoA synthetases has been hypothesized to channel fatty acids to different metabolic fates by activating the fatty acids at different subcellular compartments ( 6 ). ACSL3 is localized on lipid droplets or endoplasmic reticulum (ER) membranes, suggesting that this enzyme is likely involved in lipid synthesis ( 7,8 ). The ACSL3 is highly expressed in prostate, skeletal muscle, testis, heart, and placenta ( 9 ). Besides activation of fatty acids, a function in transport of fatty acids has been indicated for the FATPs and members of the ACSL family. Forced expression of mammalian ACSL1, ACSL4, and ACSL6 in yeast cells lacking native long-chain acyl-CoA activity lead to enhanced fatty acid uptake ( 10 ). ACSL3 has been associated with the biosynthesis of neutral lipids in hepatocytes ( 8 ); however, no information is available regarding its role on activation and uptake of fatty acids by human placental trophoblasts.LXR ␣ and LXR ␤ are nuclear receptors that are activated by oxysterols, which are oxidized cholesterol deriva- The participation of fatty acids in most metabolic pathways, including ␤ -oxidation and biosynthesis of complex lipids (such as triacylglycerols and phospholipids), requires their activation by addition of a CoA group. Mammals express three related families of proteins able to activate long chain fatty acids: the long-chain acyl-CoA synThis work was supported by grants from the

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Identification of human low‐density lipoprotein receptor as a novel target gene regulated by liver X receptor alpha

Cited by 39 publications

References 18 publications

Dual Mechanisms for the Fibrate-mediated Repression of Proprotein Convertase Subtilisin/Kexin Type 9

Dual Mechanisms for the Fibrate-mediated Repression of Proprotein Convertase Subtilisin/Kexin Type 9

Sterol-mediated Regulation of Human Lipin 1 Gene Expression in Hepatoblastoma Cells

Activation of LXR increases acyl-CoA synthetase activity through direct regulation of ACSL3 in human placental trophoblast cells

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