8, 10–12 Some animals were treated with recombinant leptin using a regimen Ku-0059436 clinical trial shown to rescue impaired regeneration in ob/ob mice (see Supporting Materials and Methods)13; some were subjected to one-third partial hepatectomy,

in which only the median lobes of the liver were resected; and some were treated with carbon tetrachloride (CCl4) (see Supporting Materials and Methods). At serial times after surgery or CCl4 administration, animals were sacrificed and plasma and liver tissue were harvested. Very little morbidity or mortality occurred in experimental animals (summarized in Supporting Materials and Methods). Three or more animals were examined at each time point for each genotype, surgical, and treatment group. All experiments were approved by the Animal Studies Committee of

Washington University and conducted in accordance with institutional guidelines and the criteria outlined in the Guide for Care and Use of Laboratory Animals (NIH publication 86-23). See Supporting Materials and Methods for detailed methods. Data were analyzed using SigmaPlot and SigmaStat software (SPSS, Chicago, IL). Unpaired Student t test for pairwise comparisons and analysis of variance for multiple groups were used with significance (alpha) set at 0.05. Data are reported as mean ± standard error. To begin to investigate the systemic metabolic response to partial Wnt inhibitor hepatectomy, total, lean, and fat mass were measured at serial times after check details surgery in wild-type C57Bl/6J mice. The results showed a stereotypical pattern of loss and recovery in each of these parameters after hepatic resection but not sham surgery (Fig. 1A-C). Maximum loss of body weight occurred 24 hours after surgery, with subsequent recovery and return to baseline by ∼2 weeks (Fig. 1A). The amount of weight lost, ∼10% of the initial body mass, was greater than that which could be explained by removal of two-thirds

of the liver (∼3% of the initial body weight). Next, changes in lean and fat mass during liver regeneration were determined using magnetic resonance (MR) spectroscopy. The results showed that both lean and fat tissue stores declined and reached their respective nadirs 24 hours after partial hepatectomy, with significantly smaller changes seen after sham surgery (Fig. 1B,C). At 24 hours, lean mass had declined by ∼10% and fat mass by ∼20% of the initial values. These catabolic changes followed the onset of hypoglycemia, detectable 3 hours after partial hepatectomy,9 and preceded the initiation of hepatocellular proliferation, which remains almost undetectable at 24 hours and does not peak until 36 hours after surgery (Fig. 4).9, 10, 12, 14 Recovery of tissue mass followed specific and distinct patterns (Fig. 1B,C), with lean mass increasing more rapidly than fat stores.

8, 10–12 Some animals were treated with recombinant leptin using a regimen Peptide 17 ic50 shown to rescue impaired regeneration in ob/ob mice (see Supporting Materials and Methods)13; some were subjected to one-third partial hepatectomy,

in which only the median lobes of the liver were resected; and some were treated with carbon tetrachloride (CCl4) (see Supporting Materials and Methods). At serial times after surgery or CCl4 administration, animals were sacrificed and plasma and liver tissue were harvested. Very little morbidity or mortality occurred in experimental animals (summarized in Supporting Materials and Methods). Three or more animals were examined at each time point for each genotype, surgical, and treatment group. All experiments were approved by the Animal Studies Committee of

Washington University and conducted in accordance with institutional guidelines and the criteria outlined in the Guide for Care and Use of Laboratory Animals (NIH publication 86-23). See Supporting Materials and Methods for detailed methods. Data were analyzed using SigmaPlot and SigmaStat software (SPSS, Chicago, IL). Unpaired Student t test for pairwise comparisons and analysis of variance for multiple groups were used with significance (alpha) set at 0.05. Data are reported as mean ± standard error. To begin to investigate the systemic metabolic response to partial Src inhibitor hepatectomy, total, lean, and fat mass were measured at serial times after find more surgery in wild-type C57Bl/6J mice. The results showed a stereotypical pattern of loss and recovery in each of these parameters after hepatic resection but not sham surgery (Fig. 1A-C). Maximum loss of body weight occurred 24 hours after surgery, with subsequent recovery and return to baseline by ∼2 weeks (Fig. 1A). The amount of weight lost, ∼10% of the initial body mass, was greater than that which could be explained by removal of two-thirds

of the liver (∼3% of the initial body weight). Next, changes in lean and fat mass during liver regeneration were determined using magnetic resonance (MR) spectroscopy. The results showed that both lean and fat tissue stores declined and reached their respective nadirs 24 hours after partial hepatectomy, with significantly smaller changes seen after sham surgery (Fig. 1B,C). At 24 hours, lean mass had declined by ∼10% and fat mass by ∼20% of the initial values. These catabolic changes followed the onset of hypoglycemia, detectable 3 hours after partial hepatectomy,9 and preceded the initiation of hepatocellular proliferation, which remains almost undetectable at 24 hours and does not peak until 36 hours after surgery (Fig. 4).9, 10, 12, 14 Recovery of tissue mass followed specific and distinct patterns (Fig. 1B,C), with lean mass increasing more rapidly than fat stores.

12 In an in vitro experiment, this drug has also been shown to be effective against HBV mutants LDE225 molecular weight resistant to lamivudine, adefovir, entecavir, and telbivudine.13 We report the results of an open-label, multicenter dose escalation study to assess the antiviral activity and safety of LB80380 for 12 weeks in CHB patients with lamivudine-resistant disease. AE, adverse event; ALT, alanine aminotransferase; CHB, chronic hepatitis B; CI, confidence interval; CrCl, creatinine clearance; DLT, dose-limiting

toxicity; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; NA, nucleoside/nucleotide analog; PP, per-protocol;

SD, standard deviation; ULN, upper limit of normal. This study was a phase II, open-label, multicenter, dose escalation study to evaluate the antiviral activity Selleckchem C646 and safety of LB80380 during a 12-week treatment period. This study was conducted at four centers in Hong Kong and Korea. Because the efficacy assessment was descriptive, the sample size calculation was based on the accuracy of the confidence interval (CI) for the primary efficacy parameter (mean reduction in HBV DNA at 12 weeks on the log10 scale). The accuracy was measured by the width of the 95% CI. The two-sided 95% CI for the mean was estimated with the assumption that the distribution of the reduction on the log scale is symmetric and normally

distributed. Assuming a potential dropout rate of at most 25% over the treatment period of 12 weeks, a minimum of twelve patients were to be enrolled into each dose group to ensure that at least nine would be evaluable. The treatment period was divided into two parts: an initial 4-week treatment period (part MCE公司 1) during which dose escalation was assessed, followed by an 8-week extension period (part 2). The treatment period was followed by a 24-week follow-up period. During the initial 4 weeks of the treatment period (part 1), patients received LB80380 together with lamivudine 100 mg once daily. The overlapping 4-week period of LB80380 and lamivudine was designed to minimize the risk of hepatitis flares that might occur if the therapy was switched directly to LB80380 monotherapy. Five doses of LB80380 were planned: 30 mg (group 1); 60 mg (group 2); 90 mg (group 3); 150 mg (group 4), and 240 mg (group 5). After completion of 4-week dosing at each level of LB80380 combined with lamivudine 100 mg in part 1, patients were given only LB80380 at the same dose for an additional 8 weeks in part 2, unless more than two patients in the group experienced dose-limiting toxicity (DLT) during part 1.

Protein expression mimicked, again, gene expression and is represented in the corresponding blots along Fig. 5 (data on protein band densitometry is provided in Supporting Information Fig. 1). As a control, IL-10 levels were measured in all cell supernatants, to evaluate free IL-10 available for its receptor to signal down. Levels were almost undetectable for the first set of cultured cells and significantly increased in the second set (data not shown). The current study shows an IL-10–mediated HO-1–induced anti-inflammatory mechanism present in patients with cirrhosis receiving norfloxacin as secondary Ensartinib mw prophylaxis for

SBP. Although the association between norfloxacin and this mechanism does not imply causality and would require Selleck CH5424802 further molecular studies, it directly associates norfloxacin with cell-modulating events in these patients. Besides its known bactericidal effect on intestinal gram-negative bacterial flora, norfloxacin has been shown to induce several immunological effects at the cellular level, decreasing proinflammatory cytokines, controlling oxidative burst, and restoring the apoptotic rate in compromised PMN cells.10 However, molecular control of the proinflammatory response remained to

be underlined in this setting. To validate our results, we compared patients with SID with a matched control group of patients with cirrhosis and ascites who are not taking norfloxacin and also with patients who have SBP, as a control group with an overt infection. In our study, an initial screening of several anti-inflammatory mediators revealed IL-10 as a significantly increased cytokine 上海皓元医药股份有限公司 in patients with SID compared with patients with noninfected AF that positively correlated with serum norfloxacin levels. IL-10 signaling induces the expression of HO-1, a stress-inducible protein with anti-inflammatory activity, through a p38 mitogen-activated

protein kinase–dependent pathway.15, 16 Accordingly, we observed that HO-1 levels were also increased in patients with SID versus patients with noninfected AF and that significantly correlated with norfloxacin serum levels as well (Fig. 1). On the contrary, different proinflammatory mediators such as NF-κB, iNOS, and COX-2 showed a norfloxacin-dependent down-regulation in patients with SID compared with patients with noninfected AF and patients with SBP (Fig. 2). From this starting point, patients with SID were distributed into three subgroups according to intracellular norfloxacin range levels to further investigate the inflammatory balance dependency on norfloxacin concentration. LPS treatment significantly increased mRNA expression levels of all proinflammatory mediators in neutrophils from patients with noninfected AF to those present in SBP whereas increasing amounts of intracellular norfloxacin limited proinflammatory molecule levels to those observed in resting cells.

Male wild-type mice (C57BL/6J) were purchased from The Jackson Laboratory or bred in the vivarium associated with our laboratory. Male Muc2−/− mice (back-crossed to C57BL/6J for more than 10 generations) were kindly

provided by Anna Velcich (Albert Einstein College of Medicine, Yeshiva University, New York, NY). Age-matched mice were used for this study. All animals received humane care in compliance with institutional guidelines. The intragastric feeding model of continuous ethanol infusion in mice has been described.28 The Lieber DeCarli diet model of alcohol feeding for 2 weeks was used to determine intestinal permeability and for an in vivo luminal killing assay. We opted to assess intestinal permeability in a complementary and noninvasive mouse model of alcoholic steatohepatitis using the Lieber DeCarli diet, because prior surgery and the implanted gastrostomy catheter could affect accurate assessment Doramapimod solubility dmso of intestinal

permeability. To avoid two surgeries in the same mouse, we also chose to assess in vivo luminal killing of bacteria in mice that were fed the Lieber DeCarli diet. Additional materials and methods are described in the Supporting Information. It has been reported that chronic alcohol feeding increases the total mucus content in the small intestine in rats.27 We have confirmed these data in humans. Alcoholics BYL719 cost show a significant increase in the thickness of the mucus layer on duodenal biopsies compared with healthy humans (Fig. 1A,B). To investigate the role of the intestinal mucus layer in experimental alcoholic liver

disease, we used mice harboring a genetic deletion medchemexpress in the Muc2 gene.25 Muc2 is the most abundant secreted mucin in the gastrointestinal tract25 and its absence results in a significantly thinner mucus layer in mice as shown by Periodic acid–Schiff (PAS) staining of the small intestine (Fig. 4A). To confirm that Muc2 expression is largely restricted to the intestine, we measured Muc2 messenger RNA levels in several organs from wild-type mice. Muc2 gene expression was highest in the small and large intestine, but it was undetectable in the liver or bone marrow–derived cells (Supporting Fig. 1A). These findings were confirmed by immunofluorescent staining. Muc2 protein was abundantly expressed in the small intestine (Supporting Fig. 1B, left panel), but undetectable in the liver of wild-type mice (Supporting Fig. 1B, right panel). Small intestine from Muc2-deficient mice served as a negative staining control (Supporting Fig. 1B, middle panel). We therefore subjected wild-type and Muc2−/− mice to the intragastric feeding model of continuous ethanol infusion for 1 week. Mice fed an isocaloric diet served as controls. Administration of ethanol lead to a comparable increase of liver weight to body weight ratio (Supporting Fig. 2A).

[12] In this study, the authors found that patients who received additional fluvastatin with PEG-IFN/RBV had

a significantly higher SVR rate than those who received PEG-IFN/RBV (63% vs 42%, P = 0.0422), even though there were comparable rapid virological response and early virological response (EVR) rates. Moreover, fluvastatin may not improve therapeutic effect in “difficult-to-treat Vincristine mouse patients” with unfavorable IL28B genotype or HCV core amino acid 70 mutant type. Because add-on fluvastatin does not improve early HCV dynamics during the first 12 weeks of PEG-IFN/RBV, the authors speculated that fluvastatin might improve SVR rate through the inhibition of viral relapse. Accordingly, the authors reexamined the data and focused on viral relapse among 67 patients who achieved virological response (complete EVR or late virological response)

in the previous study. As expected, the addition of fluvastatin to PEG-IFN/RBV significantly lowers the relapse rate of CHC patients, and absence of fluvastatin (P = 0.027, odds ratio [OR] = 3.98, 95% confidence interval [CI] = 1.05–15.1) and low total ribavirin dose (P = 0.002, OR = 2.41, 95% CI = 1.38–4.19) were identified as independent predictors for viral relapse. Therefore, they concluded that “add-on fluvastatin” may significantly suppress viral relapse in CHC patients receiving PEG-IN/RBV therapy. Although the addition of first-generation protease inhibitors has greatly improved the therapeutic efficacy of PEG-IFN/RBV Selleck CH5424802 (from 20–50% to 50–70% with genotype 1 HCV) and become current SOC in many Western countries, considering the expense, frequency, and severity of adverse reactions of PEG-IFN/RBV/protease inhibitor “triple therapy”[13] and the high prevalence

medchemexpress of IL28B favorable genotype in the Asia Pacific region,[14] the present findings are encouraging. Fluvastatin in combination with PEG-IFN/RBV may be an alternative and affordable option, being beneficial for most chronic HCV genotype 1 patients who have IL28B favorable genotype. Nevertheless, several issues need be clarified before drawing definite conclusions. First, the authors prescribed daily ribavirin of 800 mg for patients weighing 60–80 kg, or 1000 mg for patients weighting >80 kg; these doses are lower than those recommended by international guidelines.[15] A lower dose of ribavirin has been reported to increase the relapse rate.[16] In addition, blood transfusion and erythropoietin[17] may be given to patients with anemia to maintaining a higher dose of ribavirin and the response rate to SOC. Therefore, whether fluvastatin could benefit patients receiving a higher dose of ribavirin remains unclear. Second, liver fibrosis stage is an important predictor for interferon-based therapy,[18] but this information was not specified in this study.

[12] In this study, the authors found that patients who received additional fluvastatin with PEG-IFN/RBV had

a significantly higher SVR rate than those who received PEG-IFN/RBV (63% vs 42%, P = 0.0422), even though there were comparable rapid virological response and early virological response (EVR) rates. Moreover, fluvastatin may not improve therapeutic effect in “difficult-to-treat www.selleckchem.com/products/ch5424802.html patients” with unfavorable IL28B genotype or HCV core amino acid 70 mutant type. Because add-on fluvastatin does not improve early HCV dynamics during the first 12 weeks of PEG-IFN/RBV, the authors speculated that fluvastatin might improve SVR rate through the inhibition of viral relapse. Accordingly, the authors reexamined the data and focused on viral relapse among 67 patients who achieved virological response (complete EVR or late virological response)

in the previous study. As expected, the addition of fluvastatin to PEG-IFN/RBV significantly lowers the relapse rate of CHC patients, and absence of fluvastatin (P = 0.027, odds ratio [OR] = 3.98, 95% confidence interval [CI] = 1.05–15.1) and low total ribavirin dose (P = 0.002, OR = 2.41, 95% CI = 1.38–4.19) were identified as independent predictors for viral relapse. Therefore, they concluded that “add-on fluvastatin” may significantly suppress viral relapse in CHC patients receiving PEG-IN/RBV therapy. Although the addition of first-generation protease inhibitors has greatly improved the therapeutic efficacy of PEG-IFN/RBV see more (from 20–50% to 50–70% with genotype 1 HCV) and become current SOC in many Western countries, considering the expense, frequency, and severity of adverse reactions of PEG-IFN/RBV/protease inhibitor “triple therapy”[13] and the high prevalence

MCE of IL28B favorable genotype in the Asia Pacific region,[14] the present findings are encouraging. Fluvastatin in combination with PEG-IFN/RBV may be an alternative and affordable option, being beneficial for most chronic HCV genotype 1 patients who have IL28B favorable genotype. Nevertheless, several issues need be clarified before drawing definite conclusions. First, the authors prescribed daily ribavirin of 800 mg for patients weighing 60–80 kg, or 1000 mg for patients weighting >80 kg; these doses are lower than those recommended by international guidelines.[15] A lower dose of ribavirin has been reported to increase the relapse rate.[16] In addition, blood transfusion and erythropoietin[17] may be given to patients with anemia to maintaining a higher dose of ribavirin and the response rate to SOC. Therefore, whether fluvastatin could benefit patients receiving a higher dose of ribavirin remains unclear. Second, liver fibrosis stage is an important predictor for interferon-based therapy,[18] but this information was not specified in this study.

This study was aimed to investigate whether DOC could enhance intestinal tumorigenesis in APCmin/+ mice, an ideal genetic model which carries a germline mutation of the APC gene. Methods: Four-week old APCmin/+ mice were treated with 0.2% DOC in drinking water for twelve weeks. Parameters of intestinal

tumor development, cell proliferation, and Wnt signaling pathways were determined. Results: The total number of the intestine tumor in the untreated group (21.50 ± 4.69) was increased by 165% by 0.2% DOC treatment (57.00 ± 3.07). All sizes of tumor (> 2 mm, 1–2 mm, and < 1 mm) were significantly increased by DOC, and tumors in middle and distal segments of small intestine were significantly increased by 152.8% and 371.3%. Importantly, pathological

see more analysis by HE staining confirmed intestinal carcinogenesis. Furthermore, the percentage of PCNA positive cells was increased by 81%. DOC treatment promoted the translocation of β-catenin from membrane to cytoplasm and nuclear, and also increased the expression of cyclin Dl, one of the key downstream moleculars of Wnt signaling [ (35.40 ± 3.02) % vs (71.93 ± 4.01) %, P < 0.001)]. Conclusion: DOC can enhance intestinal tumorigenesis in APCmin/+ mice, which is associated with its promotion of tumor cell proliferation through regulation Selleckchem ALK inhibitor of Wnt signaling pathways. Key Word(s): 1. Deoxycholate; 2. intestinal neoplasms; 3. Wnt signal pathway; 4. APCmin/+ mice; Presenting Author: YUTA KOUYAMA Additional Authors: SHIN-EI KUDO, HIDEYUKI MIYACHI, YUIJENNIFER OKA, AKIHIRO YAMAUCHI, KATSURO ICHIMASA, SHINGO MATSUDAIRA, HIROMASA OIKAWA, TOMOKAZU HISAYUKI, TAKEMASA HAYASHI, KUNIHIKO WAKAMURA, EIJI HIDAKA, FUMIO ISHIDA, SHIGEHARU HAMATANI Corresponding Author: YUTA KOUYAMA Affiliations: Digestive Disease Center Showa University Northern Yokohama Hospital Objective: Recently, the existence of depressed-type colorectal carcinomas has been revealed and an increasing number of depressed lesions were reported. They are called “de novo” carcinomas. The aim is to clarify the pathological features of depressed-type

submucosal-invasive carcinomas. Methods: A total of 19452 colorectal neoplasms excluding advanced carcinomas were resected endoscopically or surgically in our Center from April 2001 to December 2012. Of these, 829 lesions were submucosal-invasive carcinomas. According to the morphological/development 上海皓元医药股份有限公司 classification, 189 lesions (22.2%) were depressed-type, 264 lesions (30.7%) were flat-type and 366 lesions (45.9%) were protruded-type. We analyzed the pathological features of these lesions. Results: The rate of vessel permeation was 63.5% in depressed-type, 32.2% in flat-type and 38.0% in protruded-type, and that of tumor budding was 36.0%, 14.8% and 16.7%, respectively. In lesions smaller than 10 mm in size, the rate of massively invasive cancers was 78.5%, 46.7% and 59.3%, respectively. In lesions smaller than 15 mm in size, 10.

This study was aimed to investigate whether DOC could enhance intestinal tumorigenesis in APCmin/+ mice, an ideal genetic model which carries a germline mutation of the APC gene. Methods: Four-week old APCmin/+ mice were treated with 0.2% DOC in drinking water for twelve weeks. Parameters of intestinal

tumor development, cell proliferation, and Wnt signaling pathways were determined. Results: The total number of the intestine tumor in the untreated group (21.50 ± 4.69) was increased by 165% by 0.2% DOC treatment (57.00 ± 3.07). All sizes of tumor (> 2 mm, 1–2 mm, and < 1 mm) were significantly increased by DOC, and tumors in middle and distal segments of small intestine were significantly increased by 152.8% and 371.3%. Importantly, pathological

AZD6244 solubility dmso analysis by HE staining confirmed intestinal carcinogenesis. Furthermore, the percentage of PCNA positive cells was increased by 81%. DOC treatment promoted the translocation of β-catenin from membrane to cytoplasm and nuclear, and also increased the expression of cyclin Dl, one of the key downstream moleculars of Wnt signaling [ (35.40 ± 3.02) % vs (71.93 ± 4.01) %, P < 0.001)]. Conclusion: DOC can enhance intestinal tumorigenesis in APCmin/+ mice, which is associated with its promotion of tumor cell proliferation through regulation Selleck Dactolisib of Wnt signaling pathways. Key Word(s): 1. Deoxycholate; 2. intestinal neoplasms; 3. Wnt signal pathway; 4. APCmin/+ mice; Presenting Author: YUTA KOUYAMA Additional Authors: SHIN-EI KUDO, HIDEYUKI MIYACHI, YUIJENNIFER OKA, AKIHIRO YAMAUCHI, KATSURO ICHIMASA, SHINGO MATSUDAIRA, HIROMASA OIKAWA, TOMOKAZU HISAYUKI, TAKEMASA HAYASHI, KUNIHIKO WAKAMURA, EIJI HIDAKA, FUMIO ISHIDA, SHIGEHARU HAMATANI Corresponding Author: YUTA KOUYAMA Affiliations: Digestive Disease Center Showa University Northern Yokohama Hospital Objective: Recently, the existence of depressed-type colorectal carcinomas has been revealed and an increasing number of depressed lesions were reported. They are called “de novo” carcinomas. The aim is to clarify the pathological features of depressed-type

submucosal-invasive carcinomas. Methods: A total of 19452 colorectal neoplasms excluding advanced carcinomas were resected endoscopically or surgically in our Center from April 2001 to December 2012. Of these, 829 lesions were submucosal-invasive carcinomas. According to the morphological/development medchemexpress classification, 189 lesions (22.2%) were depressed-type, 264 lesions (30.7%) were flat-type and 366 lesions (45.9%) were protruded-type. We analyzed the pathological features of these lesions. Results: The rate of vessel permeation was 63.5% in depressed-type, 32.2% in flat-type and 38.0% in protruded-type, and that of tumor budding was 36.0%, 14.8% and 16.7%, respectively. In lesions smaller than 10 mm in size, the rate of massively invasive cancers was 78.5%, 46.7% and 59.3%, respectively. In lesions smaller than 15 mm in size, 10.

To control the onset and progression of fatty liver, it is necessary to understand the precise mechanism of lipid accumulation in the liver. Recent data indicate that a network interconnected with the adenosine monophosphate (AMP)-activated protein kinase (AMPK) and the nuclear hormone

receptor liver X receptor α (LXRα; NR1H3) plays key roles in the regulation of hepatic lipogenesis. 2-5 AMPK is a major regulator of carbohydrate and fat metabolism, serving as a metabolic master switch in response to alterations in cellular energy charge. 6 AMPK is activated by metabolic stimuli, such as hypoxia and glucose deprivation, and by energy-balancing cytokines including leptin and adiponectin, resulting in the decrease of hepatic triglyceride storage and levels of plasma fatty acids and triglycerides. 5 When cellular adenosine triphosphate (ATP) is consumed, it leads to a rise in AMP, resulting in an increase see more in the AMP/ATP ratio, which further causes decreases in reduced nicotinamide adenine dinucleotide (NADH) associated with increases in the NAD+/NADH ratio. These cellular energy status factors and redox potential are the major stimuli that activate AMPK. 5, 6 AMPK inactivates acetyl-CoA

carboxylase 1 (ACC1) by direct protein phosphorylation, and suppresses the expression of lipogenic genes, including the sterol regulatory element binding protein-1 (SREBP-1), the carbohydrate response element binding protein, and fatty acid synthase (FAS), thereby inhibiting fatty acid synthesis. 5, 7 It was recently reported that the antisteatogenic function of AMPK includes suppression Decitabine cell line of LXRα and its downstream genes. AMPK phosphorylates 上海皓元医药股份有限公司 LXRα directly at a threonine residue, which results in the inactivation of LXRα. 4 It also phosphorylates and inhibits SREBP-1, to attenuate hepatic steatosis. 8 AMPK suppresses the LXR-dependent activation of the SREBP-1 promoter and the proteolytic cleavage of SREBP-1c to its mature form. 9 LXRα functions as a lipid sensor that enhances hepatic fatty

acid synthesis and hypertriglycemia. 10, 11 LXRα activates the transcriptional expression of SREBP-1c, which subsequently induces FAS, ACC, and steroyl-CoA desaturase (SCD). LXRα binds directly to cis elements on the promoters of lipogenic genes, such as SREBP-1c, FAS, and ACC, leading to transcriptional activation of these genes. 12-14 Oxysterols produced naturally, such as 22(R)-hydroxycholesterol (HC), 24(S)-HC, and 24(S),25-epoxycholesterol, and synthetic compounds, such as TO901317 and GW3965, are known ligands of LXRα. 11, 15, 16 Thus, pharmacological strategies that activate AMPK, but repress LXRα, may provide a valuable opportunity to control fatty liver disease. The retinoic acid receptor–related orphan receptor α (RORα; NR1F1) is a member of the steroid/thyroid hormone receptor superfamily of transcriptional factors.