Differential effects of pharmacological liver X receptor activation on hepatic and peripheral insulin sensitivity in lean and<i>ob/ob</i>mice

Grefhorst, Aldo; Dijk, Theo H. van; Hammer, A; Sluijs, Fjodor H. van der; Havinga, Rick; Havekes, Louis M.; Romijn, Johannes A.; Groot, P.H.E.; Reijngoud, Dirk-Jan; Kuipers, Folkert

doi:10.1152/ajpendo.00165.2005

Cited by 102 publications

(106 citation statements)

References 48 publications

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“…Differential effects of pharmacological NR1HR activation on insulin sensitivity in normal or insulin-resistant conditions have also been detected in other studies. For instance, NR1HR agonists lowered blood glucose levels and improved whole-body insulin sensitivity in ob/ob mice, but not in lean mice [32]. However, recent studies have shown that NR1HR agonists may lead to increased utilisation of lipids and glucose in human skeletal muscle cells, without affecting the mechanism of action of insulin [33].…”

Section: Discussionmentioning

confidence: 99%

Liver X receptor agonists ameliorate TNFα-induced insulin resistance in murine brown adipocytes by downregulating protein tyrosine phosphatase-1B gene expression

et al. 2006

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Aims/hypothesis The nuclear receptors, including nuclear receptor subfamily 1, group H, member 3 (NR1HR, also known as liver X receptor [LXR]), are sensors of cholesterol metabolism and lipid biosynthesis that have recently been proposed as insulin sensitisers. TNFα has been described as a link between obesity and the development of insulin resistance, an important contributor to the pathogenesis of type 2 diabetes. Therefore, we decided to investigate the ability of NR1HR agonists to ameliorate TNFα-induced insulin resistance in brown adipocytes. Methods Primary brown adipocytes from rat fetuses, and from wild-type neonate mice and neonate mice deficient in the gene encoding protein tyrosine phosphatase-1B (Ptpn1, also known as Ptp1b) were cultured in the absence or presence of TNFα and different nuclear receptor agonists. Among them, the unrelated NR1HR ligands T0901317, GW3965 and (22R)-hydroxycholesterol were tested. After insulin stimulation, glucose uptake and solute carrier family 2 (facilitated glucose transporter), member 4 (SLC2A4, formerly known as GLUT4) translocation were measured. Next the insulin signalling cascade was determined by submitting cells to lysis, immunoprecipitation and immunoblotting. Results NR1HR agonists ameliorate TNFα-induced insulin resistance restoring completely insulin-stimulated glucose uptake and SLC2A4 translocation to plasma membrane. This effect is parallel to the recovery of the insulin cascade insulin receptor/IRS-2/phosphatidylinositol 3-kinase/protein kinase B, and could be due to the fact that T0901317 prevents the increase of PTPN1 production and phosphatase activity produced by TNFα. In this regard, Ptpn1-deficient brown adipocytes showed protection against insulin resistance by TNFα. Moreover, we observed that T0901317 produced in itself a significant increase over basal glucose uptake consistent with an increase of SLC2A4 protein content in plasma membrane, attributable to the activation of protein kinase ζ and/or the increase of Slc2a4 expression. Conclusions/interpretation Nuclear receptors NR1HR are interesting potential targets for drug treatment of insulin resistance. Keywords

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Section: Discussionmentioning

confidence: 99%

Liver X receptor agonists ameliorate TNFα-induced insulin resistance in murine brown adipocytes by downregulating protein tyrosine phosphatase-1B gene expression

et al. 2006

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“…Hyperinsulinemic euglycemic clamps were performed in a separate group of mice as described earlier (8). Mice were fasted from 11 p.m. to 8 a.m. the next day with drinking water available.…”

Section: Animals and Diets-f2 Male Lxr␣mentioning

confidence: 99%

“…In the past years, several studies have been published that point toward a role of LXRs in the control of glucose homeostasis. These studies showed that pharmacological LXR activation improves glycemic control in diabetic rodent models by increasing peripheral glucose disposal (8,9) and/or inhibition of hepatic gluconeogenesis (9 -12). Mitro et al (13) recently reported that physiologically relevant concentrations of either glucose or glucose 6-phosphate (G6P) are able to bind and activate LXR in HepG2 cells.…”

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confidence: 99%

Lxrα Deficiency Hampers the Hepatic Adaptive Response to Fasting in Mice

Oosterveer¹,

Dijk

Grefhorst³

et al. 2008

Journal of Biological Chemistry

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Besides its well established role in control of cellular cholesterol homeostasis, the liver X receptor (LXR) has been implicated in the regulation of hepatic gluconeogenesis. We investigated the role of the major hepatic LXR isoform in hepatic glucose metabolism during the feeding-to-fasting transition in vivo. In addition, we explored hepatic glucose sensing by LXR during carbohydrate refeeding. Lxr␣ ؊/؊ mice and their wildtype littermates were subjected to a fasting-refeeding protocol and hepatic carbohydrate fluxes as well as whole body insulin sensitivity were determined in vivo by stable isotope procedures. Lxr␣ ؊/؊ mice showed an impaired response to fasting in terms of hepatic glycogen depletion and triglyceride accumulation. Hepatic glucose 6-phosphate turnover was reduced in 9-h fasted Lxr␣ ؊/؊ mice as compared with controls. Although hepatic gluconeogenic gene expression was increased in 9-h fasted Lxr␣ ؊/؊ mice compared with wild-type controls, the actual gluconeogenic flux was not affected by Lxr␣ deficiency. Hepatic and peripheral insulin sensitivity were similar in Lxr␣ ؊/؊ and wildtype mice. Compared with wild-type controls, the induction of hepatic lipogenic gene expression was blunted in carbohydraterefed Lxr␣ ؊/؊ mice, which was associated with lower plasma triglyceride concentrations. Yet, expression of "classic" LXR target genes Abca1, Abcg5, and Abcg8 was not affected by Lxr␣ deficiency in carbohydrate-refed mice. In summary, these studies identify LXR␣ as a physiologically relevant mediator of the hepatic response to fasting. However, the data do not support a role for LXR in hepatic glucose sensing.Liver X receptors ␣ and ␤ (LXR␣/␤, 2 NR1H3/NR1H2) are important players in the transcriptional control of various metabolic pathways. LXR␣ is predominantly expressed in liver, intestine, and adipose tissue but is also present in kidney, lung, and spleen. LXR␤ is expressed in almost all tissues and organs (1, 2). LXRs can be activated by oxidized cholesterol metabolites (oxysterols), which have been identified to be their natural ligands. Hence, LXRs act as intracellular "cholesterol sensors" (3). LXRs induce lipogenic gene expression upon activation, both directly (4) and indirectly via the transcription factors sterol regulatory element binding protein-1c (SREBP-1c) and carbohydrate response element binding protein (ChREBP) (4 -7). Both SREBP-1c and ChREBP are involved in control of the conversion of glucose into fatty acids. Thus, LXRs coordinate the interactions between sterol and fatty acid metabolism, for instance to enable cholesterol ester formation during cellular cholesterol overload. In the past years, several studies have been published that point toward a role of LXRs in the control of glucose homeostasis. These studies showed that pharmacological LXR activation improves glycemic control in diabetic rodent models by increasing peripheral glucose disposal (8, 9) and/or inhibition of hepatic gluconeogenesis (9 -12). Mitro et al. (13) recently reported that physiologically relevant co...

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“…The expression of LXRa is well correlated with that of GLUT4 mRNA level during adipocyte differentiation (74) and animal models of type 2 diabetes or obesity (75). LXRa increases basal glucose uptake and glycogen synthesis in 3T3-L1 adipocytes (76).…”

Section: Liver X Receptor Amentioning

confidence: 99%

“…LXRa increases basal glucose uptake and glycogen synthesis in 3T3-L1 adipocytes (76). The expression of GLUT4 gene in the adipose tissue is directly regulated by both LXRa and LXRb but the basal GLUT4 gene expression is selectively dependent on the LXRa (75). LXR responsive element (LXRE) is found in the human (7473/7457) and mouse (7417/7402) GLUT4 promoters, which bind LXRa (77).…”

Section: Liver X Receptor Amentioning

confidence: 99%

Regulation of glucose transporter type 4 isoform gene expression in muscle and adipocytes

Kwon

Kim

et al. 2007

IUBMB Life

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SummaryThe gene expression of glucose transporter type 4 isoform (GLUT4) is known to be controlled by metabolic, nutritional, or hormonal status. Understanding the molecular mechanisms governing GLUT4 gene expression is critical, because glucose disposal in the body depends on the activities of GLUT4 in the muscle and adipocytes. The GLUT4 activities are regulated by a variety of mechanisms. One of them is transcriptional regulation. GLUT4 gene expression is regulated by a variety of transcriptional factors in muscle and adipose tissue. These data are accumulating regarding the transcriptional factors regulating GLUT4 gene expression. These include MyoD, MEF2A, GEF, TNF-a, TR-1a, KLF15, SREBP-1c, C/EBP-a, O/E-1, free fatty acids, PAPRg, LXRa, NF-1, etc. These factors are involved in the positive or negative regulation of GLUT4 gene expression. In addition, there is a complex interplay between these factors in transactivating GLUT4 promoter activity. Understanding the mechanisms controlling GLUT4 gene transcription in these tissues will greatly promote the potential therapeutic drug development for obesity and T2DM.

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Differential effects of pharmacological liver X receptor activation on hepatic and peripheral insulin sensitivity in lean andob/obmice

Abstract: Kuipers. Differential effects of pharmacological liver X receptor activation on hepatic and peripheral insulin sensitivity in lean and ob/ob mice.

Cited by 102 publications

References 48 publications

Liver X receptor agonists ameliorate TNFα-induced insulin resistance in murine brown adipocytes by downregulating protein tyrosine phosphatase-1B gene expression

Liver X receptor agonists ameliorate TNFα-induced insulin resistance in murine brown adipocytes by downregulating protein tyrosine phosphatase-1B gene expression

Lxrα Deficiency Hampers the Hepatic Adaptive Response to Fasting in Mice

Regulation of glucose transporter type 4 isoform gene expression in muscle and adipocytes

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