Activating Signal Cointegrator 2 Required for Liver Lipid Metabolism Mediated by Liver X Receptors in Mice

Kim, Seung Whan; Park, Keunhee; Kwak, Eunyee; Choi, Eunho; Lee, Seung‐Hee; Ham, Jungyeob; Kang, Heonjoong; Kim, Jong Man; Hwang, Seung Yong; Kong, Young Yun; Lee, Keesook; Lee, Jae Woon

doi:10.1128/mcb.23.10.3583-3592.2003

Cited by 46 publications

(63 citation statements)

References 57 publications

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“…However, recent data show that in its promoter, the INSIG 2 gene presents some responsive boxes to transcription factors and nuclear receptors, such as the heterodimer retinoid X receptorvitamin D receptor (RXR-VDR), peroxisome proliferatoractivated receptors (PPARs), retinoic acid receptors (RARs; Lee et al 2005), liver X receptor (LXR; Kim et al 2003), and farnesoid X receptor (FXR; Hubbert et al 2007).…”

Section: Discussionmentioning

confidence: 99%

Sex differences in hepatic regulation of cholesterol homeostasis

Marinis¹,

Martini²,

Trentalance³

et al. 2008

Journal of Endocrinology

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Physiological sex differences may influence metabolic status and then alter the onset of some diseases. According to recent studies, it is now well established that females are more protected from hypercholesterolemia-related diseases, such as cardiovascular diseases until menopause. Female protection from hypercholesterolemia is mediated by the hypolipidemic properties of estrogens, even if mechanisms underlying this protection remain still debated. Even though the regulatory mechanisms of cholesterol homeostasis maintenance are well known, few data are available on the supposed differences between male and female in these processes. So, the aim of this work was to define, through an in vivo study, the putative sex-dependent regulation of the processes underlying cholesterol homeostasis maintenance. We examined 3-hydroxy 3-methylglutaryl coenzyme A reductase and its regulatory protein network as well as the amount of low-density lipoprotein receptor and cholesterol. The study was conducted in the liver and plasma of male and female rats, on adults and during postnatal development, and on 17-b-estradiol-treated male rats. Our data support that physiological differences in proteins involved in cholesterol balance are present between the sexes and, in particular, 3-hydroxy 3-methylglutaryl coenzyme A reductase shows lower activity and expression in female and 17-b-estradioltreated male rats than in adult untreated male. Our data suggest that sex differences in enzyme expression depend on variation in regulatory proteins and seem to be related to estrogen presence. This work adds new evidence in the complicated picture of sex-dependent cellular physiology and establishes a new role for reductase regulatory proteins as a link between estrogen protective effects and cholesterol homeostasis.

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Section: Discussionmentioning

confidence: 99%

Sex differences in hepatic regulation of cholesterol homeostasis

Marinis¹,

Martini²,

Trentalance³

et al. 2008

Journal of Endocrinology

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“…Generation methods for DN2 Tg (25) and ASC-2 ϩ/Ϫ mice (28) have been described previously. Otsuka Long-Evans Tokushima Fatty (OLETF) and Long-Evans Tokushima Otsuka (LETO) rats were obtained from the Otsuka Research Institute (Japan); Sprague-Dawley (SD) rats were purchased from Orient, Ltd. (Korea).…”

Section: Animalsmentioning

confidence: 99%

“…In this case, DN1 competitively blocked the interaction of these receptors with the full-length endogenous ASC-2 (24). Similarly, Tg mice overexpressing ASC-2 fragment DN2 (the ASC-2 residues 1,431 to 1,511 containing the C-terminal NR box) were impaired in their transactivation by LXRs (25). These two dominant negatives, DN1 and DN2, appeared to be specific to ASC-2 because they were not competed by other LXXLL-type coactivators such as SRC-1 and TRAP220.…”

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confidence: 99%

“…However, because of this early lethality, the use of these knockout mice in further studies of the physiological functions of ASC-2 has been limited. Thus, we took an alternative transgenic (Tg) approach, in which dominant-negative fragments of ASC-2 were overexpressed in mice (24,25). Tg mice overexpressing ASC-2 fragment DN1 (the ASC-2 residues 849 to 929 containing the N-terminal LXXLL motif) but not DN1/m (in which the LXXLL sequences were mutated to LXXAA to disable receptor binding) were significantly impaired in many signaling pathways mediated by retinoic acid and other receptors.…”

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confidence: 99%

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Regulation of Insulin Secretion and β-Cell Mass by Activating Signal Cointegrator 2

Yeom

Kim

et al. 2006

Molecular and Cellular Biology

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Activating signal cointegrator 2 (ASC-2) is a transcriptional coactivator of many nuclear receptors (NRs) and other transcription factors and contains two NR-interacting LXXLL motifs (NR boxes).In the pancreas, ASC-2 is expressed only in the endocrine cells of the islets of Langerhans, but not in the exocrine cells. Thus, we examined the potential role of ASC-2 in insulin secretion from pancreatic ␤-cells. Overexpressed ASC-2 increased glucose-elicited insulin secretion, whereas insulin secretion was decreased in islets from ASC-2 ؉/؊ mice. DN1 and DN2 are two dominant-negative fragments of ASC-2 that contain NR boxes 1 and 2, respectively, and block the interactions of cognate NRs with the endogenous ASC-2. Primary rat islets ectopically expressing DN1 or DN2 exhibited decreased insulin secretion. Furthermore, relative to the wild type, ASC-2 ؉/؊ mice showed reduced islet mass and number, which correlated with increased apoptosis and decreased proliferation of ASC-2 ؉/؊ islets. These results suggest that ASC-2 regulates insulin secretion and ␤-cell survival and that the regulatory role of ASC-2 in insulin secretion appears to involve, at least in part, its interaction with NRs via its two NR boxes.Type 2 diabetes is the most common form of diabetes and is a disorder of glucose homeostasis resulting from insulin resistance and relative insulin deficiency (52). Insulin secretion is affected by metabolic signals and transcription factors that are necessary for proper differentiation and growth of various types of pancreatic islet cells (10). The main intracellular signals for insulin secretion derive from glucose metabolism. Glucose metabolism generates oscillations in the ATP/ADP ratio, which lead to the opening and closing of ATP-sensitive K ϩ channels and produce subsequent oscillations in membrane potential, cytoplasmic calcium concentration, and insulin release (7).Studies of human mutations and knockout mice revealed several transcription factors that play crucial roles in pancreatic development, such as PDX-1 (also known as IPF-1) (21), Nkx2.2 (50), Pax4 (47), neurogenin3 (15), and NeuroD (40). The significance of transcription factors in pancreatic development was further reinforced by the analysis of mutations in patients with maturity-onset diabetes of the young (MODY).MODY is a monogenic type of diabetes characterized by early onset, autosomal dominant inheritance and impaired insulin secretion. Although the MODY2 gene encodes a glucokinase specific to the liver and ␤-cells (3), the remaining five MODY genes encode the transcription factors hepatic nuclear factor

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“…Preferential functional association between particular nuclear receptors and coactivators may promote the specific regulation of individual genes under various conditions (6,7). At present, a limited amount of information is available regarding coactivators of LXR and their mechanistic and physiological roles in LXR-mediated transactivation (8,9).…”

Section: Introductionmentioning

confidence: 99%