Liver X receptors (LXRs) are members of the nuclear receptor superfamily defined as ligand-activated transcription factors. LXR ␣ (NR1H3) and LXR ␤ (NR1H2) (1-3) belong to a subclass that form obligate heterodimers with retinoid X receptors (RXRs). They share significant amino acid identity in their DNA and ligand binding domains and are highly conserved between human and rodent species (3). The elucidation of their role as key regulators of cholesterol homeostasis followed from the recent identification of oxysterols as physiological ligands for LXR (4-7).LXR nuclear receptors act as a transcriptional master switch for the coordinated regulation of genes involved in cellular cholesterol homeostasis, cholesterol transport, catabolism, and absorption (8, 9). Several LXR-responsive target genes, ATP binding cassette proteins, ABCA1 (8, 10-12) and ABCG1 (11, 13), cholesteryl ester transfer protein (CETP) (14), and apolipoprotein E (apoE) (15), with defined roles in the reverse cholesterol transport (RCT) process, govern the transport of excess cholesterol for eventual uptake and elimination by the liver. The ultimate disposal of this excess cholesterol returning to liver, its conversion to bile acids for secretion into bile, and its final elimination in feces are also under LXR control in some species. LXR-mediated upregulation of cholesterol 7 ␣ -hydroxylase (cyp7a), the rate-limiting enzyme for bile acid synthesis, correlates with resistance to dietary cholesterol and atherosclerosis (5, 16) in mice. The proximal promoter of the human gene does not contain an LXRE and consequently is not regulated by oxysterols or LXR. Thus, the regulation of murine and human CYP7A1 genes differs. A role for LXR target genes in the modulation of cholesterol absorption has also been implicated for ABCA1, ABCG5, and ABCG8 (8,17,18).The identification of LXR nuclear receptors as direct regulators of ABC transporter gene expression focused attention on their potentially critical role in peripheral macrophages (8, 10-13). Here, the membrane-bound ATP binding cassette protein (ABCA1) initiates the process of cholesterol elimination from peripheral tissues. The ABCA1 Abbreviations: ACC, acetyl-CoA carboxylase; acLDL, acetylated low density lipoprotein; apoE, apolipoprotein E; CETP, cholesteryl ester transfer protein; cyp7a, cholesterol 7 ␣ -hydroxylase; DMHCA, N,Ndimethyl-3 ␤ -hydroxycholenamide; LXR, liver X receptor; RCT, reverse cholesterol transport; RXR, retinoid X receptor; SREBP-1c, sterolresponse element binding protein 1c.

The nuclear receptors liver X receptor (LXR) LXR␣ and LXR␤ are differentially expressed ligand-activated transcription factors that induce genes controlling cholesterol homeostasis and lipogenesis. Synthetic ligands for both receptor subtypes activate ATP binding cassette transporter A1 (ABCA1)-mediated cholesterol metabolism, increase reverse cholesterol transport, and provide atheroprotection in mice. However, these ligands may also increase hepatic triglyceride (TG) synthesis via a sterol response element binding protein 1c (SREBP-1c)-dependent mechanism through a process reportedly regulated by LXR␣. We studied pan-LXR␣/␤ agonists in LXR␣ knockout mice to assess the contribution of LXR␤ to the regulation of selected target genes. In vitro dose-response studies with macrophages from LXR␣Ϫ/Ϫ and ␤Ϫ/Ϫ mice confirm an equivalent role for LXR␣ and LXR␤ in the regulation of ABCA1 and SREBP-1c gene expression. Cholesterol-efflux studies verify that LXR␤ can drive apoA1-dependent cholesterol mobilization from macrophages. The in vivo role of LXR␤ in liver was further evaluated by treating LXR␣Ϫ/Ϫ mice with a pan-LXR␣/␤ agonist. Highdensity lipoprotein (HDL) cholesterol increased without significant changes in plasma TG or very low density lipoprotein. Analysis of hepatic gene expression consistently revealed less activation of ABCA1 and SREBP-1c genes in the liver of LXR␣ null animals than in treated wild-type controls. In addition, hepatic CYP7A1 and several genes involved in fatty acid/TG biosynthesis were not induced. In peripheral tissues from these LXR␣-null mice, LXR␤ activation increases ABCA1 and SREBP-1c gene expression in a parallel manner. However, putative elevation of SREBP-1c activity in these tissues did not cause hypertriglyceridemia. In summary, selective LXR␤ activation is expected to stimulate ABCA1 gene expression in macrophages, contribute to favorable HDL increases, but circumvent hepatic LXR␣-dominated lipogenesis.There is great interest in targeting LXR nuclear receptors and their modulation for the treatment of atherosclerosis. These transcription factors play a critical role in the control of cholesterol homeostasis and have been the topic of several recent reviews (Jaye,

Studies were designed to examine the effect of a selective endothelinA (ETA) receptor antagonist, BQ123, on severe postischemic acute renal failure (ARF) in Sprague-Dawley rats. Severe ARF was induced in uninephectomized, chronically instrumented rats by 45-min renal artery occlusion. BQ123 (0.1 mg/kg. min) or vehicle was infused intravenously for 3 h on the day after ischemia. Measurements before infusion (24 h control) showed a 98% decrease in glomerular filtration rate (GFR), increase in fractional excretion of sodium from 0.6 to 39%, and in plasma K+ from 4.3 to 6.5 mEq/liter. All vehicletreated rats died in 4 d because of continuous deterioration of renal function, resulting in an increase of plasma K+ to fatal levels (> 8 mEq/liter). Infusion of BQ123 significantly improved survival rate (75%) by markedly improving tubular reabsorption of Na' and moderately increasing GFR and K+ excretion. Plasma K+ returned to basal levels by the 5th d after ischemia. Improved tubular function was followed by gradual recovery in GFR and urinary concentrating mechanism.Additional data from renal clearance studies in rats with moderate ARF (30-min ischemia) and in normal rats with intact kidneys showed that ETA receptor blockade increases Nan reabsorption and has no effect on renal hemodynamics. These results indicate that in the rat, the ETA receptor subtype mediates tubular epithelial function, and it plays a significant role in the pathogenesis of ischemia-induced ARF. Treatment with the selective ETA receptor antagonist reverses deteriorating tubular function in established ARF, an effect of possible therapeutic significance. (J. Clin. Invest. 1994. 93:900-906.) Key words: ischemia * moderate and severe acute renal failure * endothelinA receptor * BQ123

Preincubation of turkey erythrocytes with catecholamines desensitizes the fi-adrenergic receptor-adenylate cyclase complex in the plasma membranes of these cells. Photoaffinity labeling of the (3-adrenergic receptors with "SI-labeled pazidobenzylcarazolol (l25I-pABC) and subsequent analysis by NaDodSO4/polyacrylamide gel electrophoresis demonstrates an altered mobility of receptor peptides from desensitized cells compared to controls [Stadel, J. M., Nambi, P., Lavin, T. N., Heald, S. L., Caron, M. G. & Lefkowitz, R. J. (1982)J. BioL Chem. 257,[9242][9243][9244][9245]. The time course of alteration in 3-adrenergic receptor mobility correlates with that for desensitization of isoproterenol-stimulated adenylate cyclase activity. The altered mobility of the receptor peptides from desensitized cells is also observed if the receptors are first purified and then photoaffinity labeled with '25I-pABC. The cyclic nucleotide analog 8-bromoadenosine 3',5'-cyclic monophosphate partially mimics catecholamines in promoting desensitization of the adenylate cyclase and modification of the receptor. Phosphorylation of the fi-adrenergic receptor in intact turkey erythrocytes was assessed by preincubating the cells with [3P]orthophosphate, desensitizing them with catecholamine, purifying the receptors, and then subjecting them to NaDodSO4/ polyacrylamide gel electrophoresis. Desensitization is associated with a 2-to 3-fold increase in 32p incorporation into the receptor, which also demonstrates the characteristic alterations in mobility.These effects are blocked by the 13-adrenergic antagonist propranolol. Purified turkey erythrocyte 13-adrenergic receptors could be phosphorylated by incubation with [y-32P]ATP and the catalytic subunit of cAMP-dependent protein kinase. The mobility of the phosphorylated receptor peptides on NaDodSO4/polyacrylamide gel electrophoresis appears to correspond to that of the desensitized receptors. These data show that catecholamine-induced desensitization of adenylate cyclase in turkey erythrocytes correlates with a stable modification of the 13-adrenergic receptor and is associated with agonist-promoted phosphorylation of ,ireceptor peptides.Prolonged exposure of target tissues to hormones or neurotransmitters attenuates the responsiveness of the tissue to subsequent challenge by these agents. This regulatory process termed "desensitization" or "refractoriness" has been studied in a wide variety of cell types (1-7). Investigations of adenylate cyclase-coupled ,B-adrenergic receptor systems indicate the existence of multiple mechanisms for desensitization (5,8,9).However, the molecular events that underlie the processes of desensitization remain to be elucidated. Recently we reported that catecholamine-induced desensitization of adenylate cyclase in turkey erythrocytes promotes a modification of the structure of /&adrenergic receptor peptides that results in decreased mobility of these peptides on NaDodSO4/polyacrylamide gel electrophoresis compared to controls (10). ,B-Adrenergic receptor pep...

This article is available online at http://www.jlr.org Supplementary key words cynomolgus monkey • dyslipidemia • fi broblast growth factor 19 • hypertriglyceridemiaAtherosclerosis is the major cause of cardiovascular disease and its incidence is on the rise due to its tight relationship to obesity and diabetes. Therapeutic interventions targeted at reducing elevated plasma low-density lipoprotein cholesterol (LDLc), the primary risk factor for development of atherosclerosis, do not eliminate cardiovascular risk particularly in several high-risk subpopulations. The statin class of drugs achieve dramatic reductions in LDLc yet reduce heart attack risk only 33% per 1.5 mmol/L reduction in LDL ( 1 ). As statins primarily limit disease progression through the inhibition of endogenous cholesterol synthesis, newer treatment modalities directed at reversing established atherosclerotic plaque are likely to provide additional benefi t and can have important clinical implications for disease management. This is exemplifi ed by the exploratory clinical studies targeting the enhancement of high-density lipoprotein ( 2 ). In this study, intravenous