Regulation of the angiopoietin-like protein 3 gene by LXR

Kaplan, Rebecca; Zhang, Theresa; Hernandez, Melba; Gan, Frank Xiaodong; Wright, Samuel D.; Waters, M. Gerard; Cai, Tian-Quan

doi:10.1194/jlr.m200367-jlr200

Cited by 104 publications

(83 citation statements)

References 29 publications

(42 reference statements)

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“…Similar findings have also been reported by others (20). Interestingly, LXR was found to upregulate angiopoietinlike protein 3 (Angptl3), a member of the family of vascular endothelial growth factors that is also a key regulator of lipid metabolism (21). The KK/San mouse strain has low levels of plasma triglycerides, total cholesterol, and nonesterified fatty acids because of a mutation in the Angptl3 gene.…”

supporting

confidence: 67%

Putative Metabolic Effects of the Liver X Receptor (LXR)

2004

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The nuclear receptors liver X receptor (LXR)␣ and LXR␤ are sensors of cholesterol metabolism and lipid biosynthesis. They have recently been found to be regulators of inflammatory cytokines, suppressors of hepatic glucose production, and involved in different cellsignaling pathways. LXR␣ is a target gene of the peroxisome proliferator-activated receptor-␥, a target of drugs used in treating elevated levels of glucose seen in diabetes. Furthermore, insulin induces LXR␣ in hepatocytes, resulting in increased expression of lipogenic enzymes and suppression of key enzymes in gluconeogenesis, including PEPCK. LXR seems to have an important role in the regulation of glucocorticoid action and a role in the overall energy homeostasis suggested by its putative regulatory effect on leptin and uncoupling protein 1. The physiological roles of LXR indicate that it is an interesting potential target for drug treatment of diabetes. Diabetes 53 (Suppl. 1):S36 -S42, 2004 T ype 2 diabetes accounts for Ͼ90% of the cases of diabetes and is caused by defective insulin secretion and insulin resistance. Type 2 diabetes is often of polygenic origin, but the molecular defects are still not fully known. However, the genetic background of maturity-onset type diabetes of the young is known.A class of nuclear receptors has recently become the focus for its important role in cholesterol, lipid, and carbohydrate metabolism, namely the liver X receptor (LXR). A number of recent studies have shown that LXR is a key player in these biological functions. The main target tissues for LXR action are liver and adipose tissue, where its function has been carefully studied, but LXR has recently been suggested to be involved in lipid and carbohydrate metabolism in muscle as well. Important target tissues of insulin action are also liver, muscle, and adipose tissue, where insulin stimulates the uptake of excess glucose from blood and inhibits hepatic glucose production. A salient feature of type 2 diabetes is insulin resistance in these tissues, which leads to hyperglycemia and hyperlipidemia, both pathological conditions where, based on recent studies, LXR may be a key player. The LXR subfamily consists of two members, LXR␣ and LXR␤, which are activated by oxysterols. Whereas LXR␤ is ubiquitously expressed, high expression of LXR␣ is restricted to liver, adipose tissue, small intestine, and macrophages. LXR target genes have been shown to be involved in lipid and cholesterol metabolism, glucose homeostasis, and inflammatory response (Table 1). This review will focus on physiological roles of LXR and highlight why LXR could be an important potential target for drug treatment of lipid and carbohydrate disorders. LXR IN CHOLESTEROL AND LIPID METABOLISMThe phenotypes of LXR knockout mice generated in our laboratory and by Mangelsdorf and colleagues have shown that LXR is important for cholesterol and lipid metabolism (1,2). These were the first of many articles reporting LXR as a sensor for metabolites of lipid and cholesterol metabolism. Thus, Mangelsdorf ...

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confidence: 67%

Putative Metabolic Effects of the Liver X Receptor (LXR)

2004

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“…3). The results of recent studies (45)(46)(47)(48) indicate that one of the factors that regulates LPL activity is angiopoietin-like proteins 3 (Ang-L3) and Ang-L4. Intravenous injection of recombinant Ang-L3 or Ang-L4 protein in mice inhibited LPL activity and concomitantly increased serum TGs (46,47).…”

Section: Figmentioning

confidence: 99%

“…On the other hand, TC and PL levels in serum were not affected by the absence of PPAR␤ under both dietary conditions. Recent reports (45)(46)(47)(48) have demonstrated that Angptl3 and Angptl4, which are synthesized and secreted by liver, inhibit LPL (but not HL) activity (which is the primary means of catabolism of TGs in VLDL into FFAs) distally in the plasma FIG. 6.…”

Section: Ppar␤-null Mice On An Hf Diet Exhibit Lowered Body Weight Anmentioning

confidence: 99%

Peroxisome Proliferator-activated Receptor β/δ Regulates Very Low Density Lipoprotein Production and Catabolism in Mice on a Western Diet

Akiyama

Lambert

Nicol

et al. 2004

Journal of Biological Chemistry

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The results of recent studies using selective agonists for peroxisome proliferator-activated receptor ␤ (PPAR␤) suggest that this receptor may have a role in regulating levels of serum lipids in animal models of obesity and insulin resistance. To further examine this possibility, serum lipid profiles of mice lacking a functional PPAR␤ receptor were determined. PPAR␤-null mice maintained on either normal chow or a 10-week high fat (HF) diet, a condition that has been shown to induce insulin resistance and obesity in mice, have elevated levels of serum triglycerides primarily associated with very low density lipoprotein (VLDL) with no difference in either total cholesterol or phospholipids. Consistent with this finding, PPAR␤-null mice on a HF-diet were shown to have an increased rate of hepatic VLDL production as well as lowered lipoprotein lipase activity in serum compared with wild-type controls. The latter parallels an increase in the hepatic expression of the genes encoding angiopoietin-like proteins 3 and 4 in PPAR␤-null mice on a HF diet, both proteins of which have recently been shown to inhibit lipoprotein lipase (LPL) activity in vivo. Consistent with elevated VLDL production, a marked increase in plasma VLDL apoB48, -E, -AI, and -AII, as well as a sharp depletion of the hepatic lipid stores was also found in PPAR␤-null mice. In addition, PPAR␤-null mice on a HF diet were shown to have increased adiposity, despite lower total body weight. Together, these results indicate a clear role for PPAR␤ in regulating levels of serum triglycerides in mice on a high fat Western diet by modulating both VLDL production and LPL-mediated catabolism of VLDL-triglycerides and also suggest a potential therapeutic role for PPAR␤ in the improvement of serum lipids in the setting of metabolic syndrome.The peroxisome proliferator-activated receptors (PPARs) 1 are members of the nuclear hormone receptor superfamily.

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“…Accumulating evidence indicates that some genes closely related to ANGPTL3, especially LXRα, ANGPTL4 and ANGPTL6, function as a new class of lipid and energy metabolism modulator (Kadomatsu et al, 2011). It has been reported that ANGPTL3 is a direct target of LXRα, which is a nuclear receptor activated by oxysterols and known to play an important role in the control of lipid homeostasis (Kaplan et al, 2003). Dahlman et al (2006) reported that LXRα mRNA levels are higher in obese women (P = 0.03) and that mutation in LXRα is associated with body mass index and obesity.…”

Section: Discussionmentioning

confidence: 99%

Tissue expression and predicted protein structures of the bovine ANGPTL3 and association of novel SNPs with growth and meat quality traits

Chen

Yang

et al. 2015

Animal

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Angiopoietin-like protein 3 (ANGPTL3) is a secreted protein that regulates lipid, glucose and energy metabolism. This study was conducted to better understand the effect of ANGPTL3 on important economic traits in cattle. First, transcript profiles for ANGPTL3 were measured in nine different Jiaxian cattle tissues. Second, polymorphisms were identified in the complete coding region and promoter region of the bovine ANGPTL3 gene in 707 cattle samples. Finally, an association study was carried out utilizing these single nucleotide polymorphisms (SNPs) to determine the effect of these SNPs on the growth and meat quality traits. Quantitative real-time PCR analysis showed that ANGPTL3 was mainly expressed in the liver. The promoter of the bovine ANGPTL3 contained several putative transcription factor binding sites (SF1, HNF-1, LXRα, NFκβ, HNF-3 and C/EBP). In total, four SNPs of the bovine ANGPTL3 gene were identified by direct sequencing. SNP1 (rs469906272: g. − 38T > C) was identified in the promoter, SNP2 (rs451104723:g.104A > T) and SNP3 (rs482516226: g.509A > G) were identified in exon 1, and SNP4 (rs477165942: g.8661T > C) was identified in exon 6. Changes in predicted protein structures due to non-synonymous SNPs were analyzed. Haplotype frequencies and linkage disequilibrium were also investigated. Analysis of four SNPs in cattle from different native Chinese breeds (Nanyang (NY) and Jiaxian (JX)) and commercial breeds (Angus (AG), Hereford (HF), Limousin (LM), Luxi (LX), Simmental (ST) and Jinnan (JN)) revealed a significant association with growth traits (including: BW and hipbone width) and meat quality traits (including: Warner-Bratzler shear force and ribeye area). Therefore, implementation of these four mutations in selection indices in the beef industry may be beneficial in selecting individuals with superior growth and meat quality traits.

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Regulation of the angiopoietin-like protein 3 gene by LXR

Abstract: Together, these studies show that Angptl3 is transcriptionally regulated by LXR, and reveals a novel mechanism by which LXR may regulate lipid metabolism.-Kaplan, R

Cited by 104 publications

References 29 publications

Putative Metabolic Effects of the Liver X Receptor (LXR)

Putative Metabolic Effects of the Liver X Receptor (LXR)

Peroxisome Proliferator-activated Receptor β/δ Regulates Very Low Density Lipoprotein Production and Catabolism in Mice on a Western Diet

Tissue expression and predicted protein structures of the bovine ANGPTL3 and association of novel SNPs with growth and meat quality traits

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