2B, Supporting Fig. 1). Again, the segregation between progressors and nonprogressors is evident. We then tested 250 proteins, 154 up-regulated and 96 down-regulated, that define the clusters shown in Fig. 2, for confounding factors. Ceritinib The signature is robust against time (Fig. 2B), and all the potential confounding clinical factors are listed in Supporting

Fig. 3. The calculation of external isolation (a measure for how well individual biologic conditions separate) and internal cohesiveness (a measure for how well members of a single biological condition cluster together), and indicated in the different panels, allow quantification of this statement when compared with Fig. 2A and 2B. In conclusion, the subset of statistically significant differentially abundant proteins may indicate whether a patient will progress to severe liver disease posttransplantation. Consistent with the literature, we observed a significantly greater mean donor age in patients with rapidly progressive fibrosis (Table 1). The biological significance of the altered protein abundance pattern described above was further investigated by classifying the associated proteins within the context of biologically relevant functions using IPA. Patients with rapid fibrosis progression exhibited an enrichment of down-regulated proteins mapping to signaling or disease

pathways associated with hepatoprotective MK-2206 manufacturer activities, whereas up-regulated proteins

mapped to various immune response pathways (Table 2 and Supporting Table 6). With regard to the medchemexpress latter, the representation of allograft rejection signaling pathways reflects the functional redundancy of proteins associated with inflammatory conditions attributed to viral recurrence or graft rejection, processes that are difficult to discern because they are histologically indistinguishable. We note that all patients received different combinations of immune-suppressing drugs, including treatment for graft rejection that trended with rapid fibrosis progression at 1 year posttransplantation (Table 1). However, we did detect differential regulation of biological processes such as proinflammatory innate immune activities and positive regulation of interferon gamma protein expression and downstream targets consistent with those described during the transcriptional deregulation associated specifically with HCV recurrence, rather than acute cellular rejection.23 Not surprisingly, patients with progressive liver disease further exhibited an enrichment of differentially regulated proteins mapping to the IPA toxicologic functional category of liver fibrosis, including proteins associated with hepatic stellate cell activation (P < 0.05), and demonstrate the possibility of detecting protein abundance profiles consistent with hepatic damage weeks or months prior to clinical evidence of liver injury.

However, in all models that we generated using this technique, transfected cells were fully differentiated hepatocytes located in zone 3 and, thus, preneoplastic lesions developed always in zone 3 vein proximity.[7] The morphological demonstration, showing that affected single cells in AKT/Notch1 mice

were never located in zone 1 but always in zone 3 (Fig. 1D-I) is a proof of the physiologic principle of the method,[6] in line with all our models,[7] and in absolute contradiction to the progenitor-cell hypothesis. Furthermore, electron microscopy showed the presence of tight junctions between transfected and normal hepatocytes (supporting Fig. 10),[2] thus indicating their hepatocellular nature. Matthias Evert, M.D.1Frank Dombrowski, M.D.1Biao

Fan, M.D., Ph.D.2Silvia Ribback, M.D.1Xin Chen, Ph.D.2Diego F. Calvisi, M.D.1 “
“T cells play a crucial role for viral clearance or persistence; however, the precise mechanisms Belnacasan cost that control their responses during viral infection remain incompletely understood. microRNAs (miR) have been implicated as key regulators controlling diverse biological processes through posttranscriptional repression. Here, we demonstrate that hepatitis C virus (HCV)-mediated decline of miR-181a expression impairs CD4+ T cell responses via over-expression of dual specific phosphatase 6 (DUSP6). Specifically, a significant decline of miR-181a expression along with over-expression of DUSP6 were observed in CD4+ T cells from chronically HCV-infected individuals compared buy GSK2118436 to healthy subjects, and the levels of miR-181a loss were found to be negatively associated with the levels of DUSP6 over-expression MCE in these cells. Importantly, reconstitution of miR-181a or blockade of DUSP6 expression

in CD4+ T cells led to improved T cell responses including enhanced CD25 and CD69 expressions, increased IL-2 expression, and improved proliferation of CD4+ T cells derived from chronically HCV-infected individuals. Since a decline of miR-181a concomitant with DUSP6 over-expression are the signature markers for age-associated T cell senescence, these findings provide novel mechanistic insights into HCV-mediated premature T cell aging via miR-181a-regulated DUSP6 signaling, and reveal new targets for therapeutic rejuvenation of impaired T cell responses during chronic viral infection. This article is protected by copyright. All rights reserved. “
“In a recent issue of Hepatology, Herrera et al.[1] reported that human bone-marrow derived mesenchymal stem cells (hMSCs) provided protection from death from fulminant liver failure (FLF) induced by intraperitoneal injection of D-galactosamine/lipopolysaccharide (GalN/LPS) in severe combined immune deficiency (SCID) mice. SCID mice lack functional T and B cells and have been used extensively in xenotransplantation. However, the mice still possess normal natural killer (NK) cells.

However, in all models that we generated using this technique, transfected cells were fully differentiated hepatocytes located in zone 3 and, thus, preneoplastic lesions developed always in zone 3 vein proximity.[7] The morphological demonstration, showing that affected single cells in AKT/Notch1 mice

were never located in zone 1 but always in zone 3 (Fig. 1D-I) is a proof of the physiologic principle of the method,[6] in line with all our models,[7] and in absolute contradiction to the progenitor-cell hypothesis. Furthermore, electron microscopy showed the presence of tight junctions between transfected and normal hepatocytes (supporting Fig. 10),[2] thus indicating their hepatocellular nature. Matthias Evert, M.D.1Frank Dombrowski, M.D.1Biao

Fan, M.D., Ph.D.2Silvia Ribback, M.D.1Xin Chen, Ph.D.2Diego F. Calvisi, M.D.1 “
“T cells play a crucial role for viral clearance or persistence; however, the precise mechanisms Ku-0059436 mw that control their responses during viral infection remain incompletely understood. microRNAs (miR) have been implicated as key regulators controlling diverse biological processes through posttranscriptional repression. Here, we demonstrate that hepatitis C virus (HCV)-mediated decline of miR-181a expression impairs CD4+ T cell responses via over-expression of dual specific phosphatase 6 (DUSP6). Specifically, a significant decline of miR-181a expression along with over-expression of DUSP6 were observed in CD4+ T cells from chronically HCV-infected individuals compared selleck chemical to healthy subjects, and the levels of miR-181a loss were found to be negatively associated with the levels of DUSP6 over-expression medchemexpress in these cells. Importantly, reconstitution of miR-181a or blockade of DUSP6 expression

in CD4+ T cells led to improved T cell responses including enhanced CD25 and CD69 expressions, increased IL-2 expression, and improved proliferation of CD4+ T cells derived from chronically HCV-infected individuals. Since a decline of miR-181a concomitant with DUSP6 over-expression are the signature markers for age-associated T cell senescence, these findings provide novel mechanistic insights into HCV-mediated premature T cell aging via miR-181a-regulated DUSP6 signaling, and reveal new targets for therapeutic rejuvenation of impaired T cell responses during chronic viral infection. This article is protected by copyright. All rights reserved. “
“In a recent issue of Hepatology, Herrera et al.[1] reported that human bone-marrow derived mesenchymal stem cells (hMSCs) provided protection from death from fulminant liver failure (FLF) induced by intraperitoneal injection of D-galactosamine/lipopolysaccharide (GalN/LPS) in severe combined immune deficiency (SCID) mice. SCID mice lack functional T and B cells and have been used extensively in xenotransplantation. However, the mice still possess normal natural killer (NK) cells.

McGovern – Employment: AbbVie Heiner Wedemeyer – Advisory Committees or Review Panels: Transgene, MSD, Roche, Gilead, Abbott, BMS, Falk,

Abbvie, Novartis, GSK; Grant/Research Support: MSD, Novartis, Gilead, Roche, Abbott; Speaking and Teaching: BMS, MSD, Novartis, ITF, Abbvie, Gilead Objective: Interferon based treatment options for HCV/HIV-1 coinfected patients (pts) have sub-optimal efficacy and limited studies have been conducted evaluating interferon-free HCV treatment regimens in this population. The 3 direct-acting antiviral (3D) regimen of ABT-450 (identified by AbbVie and Enanta; co-dosed with ritonavir), ombitasvir, and dasabuvir with riba-virin (RBV) achieves high sustained virologic response (SVR) rates in HCV genotype (GT) 1-monoinfected pts. The 3D+RBV regimen

was assessed in adults with HCV GT1/HIV-1 coinfec-tion see more with and without cirrhosis. Methods: TURQUOISE-I is a randomized, open-label study evaluating the 3D+RBV regimen for 12 or 24 weeks. HCV treatment-naïve or pegIFN/RBV-ex-perienced pts, with or without Child-Pugh A cirrhosis, CD4+ count ≥200 cells/mm3 or CD4+ % ≥14%, and plasma HIV-1 RNA suppressed on a stable atazanavir- or raltegravir-inclu-sive Palbociclib antiretroviral (ART) regimen were included. The primary endpoint is sustained virologic response weeks post-treatment (SVR12). Results: Among pts treated with 3D+RBV for 12 weeks, 29/31 (93.5%) achieved SVR12. One pt withdrew consent prior to finishing treatment but had an undetectable

HCV RNA at last study visit (week 10). Another pt experienced relapse at post-treatment week 2. Among pts receiving 24 weeks of medchemexpress treatment, 31/32 (96.9%) achieved EOTR; 1 pt experienced on-treatment HCV breakthrough at week 16. Adverse events (AEs) were generally mild, and no serious AE or discontinuations due to an AE were reported. The most common AEs were fatigue, insomnia, and nausea. Elevation in total bilirubin was the most common laboratory abnormality, occurring predominantly in pts receiving atazanavir. To date, 1 pt in each arm has had a confirmed HIV-1 RNA ≥40 copies/ mL (but <200 copies/mL) that re-suppressed while maintaining the same HIV-1 ART regimen without 3D+RBV interruption. Conclusions: In treatment-naïve and -experienced GT1 HCV/ HIV-1 coinfected pts with or without cirrhosis, the high rates of virologic response and low rate of treatment discontinuation were consistent with those in HCV GT1-monoinfected populations receiving 3D+RBV. Disclosures: David L. Wyles – Advisory Committees or Review Panels: Bristol Myers Squibb, Merck, AbbVie, Janssen, Gilead; Grant/Research Support: Gilead, Merck, Vertex, Pharmassett, AbbVie Mark S. Sulkowski – Advisory Committees or Review Panels: Merck, AbbVie, Idenix, Janssen, Gilead, BMS, Pfizer; Grant/Research Support: Merck, AbbVie, BIPI, Vertex, Janssen, Gilead, BMS Joseph J.

47 Many reports have subsequently been published, and a consensus statement was published asserting that genotype 1b is more resistant to IFN than genotype 2 and 3 and

recommending combination therapy with ribavirin.48 With the advent of peg-IFN plus ribavirin combination therapy, the eradication rate of the virus has improved. The response rate of the combination therapy is also dependent on HCV genotype (Table 1), as reflected in three consensus statements published in different geographic areas.69–71 Specific nucleotide and amino acid substitutions have been reported to be correlated with the effect of both IFN therapy and peg-IFN plus ribavirin combination therapy. Enomoto et al. first noted that outcome of IFN therapy is related to the total number of amino Daporinad mw acid substitutions in a 40 amino acid stretch

selleck inhibitor of the NS5A region.72,73 They designated this region the interferon sensitivity determining region (ISDR). Following this discovery, several other regions were also reported to correlate with the effect of IFN or peg-IFN plus ribavirin combination therapy. Corresponding amino acid sequences that have been reported so far are listed in Table 2. Recently, Enomoto et al. compared 88 full-length genotype 1b nucleotide sequences obtained from patients treated with peg-IFN plus ribavirin combination therapy and found that only core and ISDR amino acid substitutions are predictive of early response to therapy.108 Substitution of core protein amino acid 70 is of particular interest, not only as a predictor of effect of peg-IFN plus ribavirin combination therapy, but also because of the curious interactions between viral and host proteins as discussed below. Recently, an association between common genetic variation in the human

IL28B locus and the effect of peg-interferon and ribavirin therapy was found.135–138 The single nucleotide polymorphisms (SNPs) in the IL28B locus that are associated with SVR following combination therapy (rs8099917T and rs12979860 C) have higher allele frequencies in Asian and Caucasian populations than in African populations, in which the response to IFN is known to be relatively poorer than other ethnic groups. rs12979860 medchemexpress has also been reported to be associated with spontaneous eradication of HCV.139 Interestingly, we found that amino acid substitutions in the core region of HCV are strongly associated with IL28B SNP genotype. As shown in Fig. 4, the T allele of SNP rs8099917 within the IL28B locus is associated with core amino acid 70 arginine, which is associated with favorable response to peg-IFN plus ribavirin combination therapy.130,131 This association of human genetic variation and viral amino acid substitutions is particularly interesting. The viral strain that is relatively more sensitive to the combination therapy is more prevalent in patients that have the SNP genotype associated with a higher eradication rate of the virus by combination therapy or spontaneous elimination.

47 Many reports have subsequently been published, and a consensus statement was published asserting that genotype 1b is more resistant to IFN than genotype 2 and 3 and

recommending combination therapy with ribavirin.48 With the advent of peg-IFN plus ribavirin combination therapy, the eradication rate of the virus has improved. The response rate of the combination therapy is also dependent on HCV genotype (Table 1), as reflected in three consensus statements published in different geographic areas.69–71 Specific nucleotide and amino acid substitutions have been reported to be correlated with the effect of both IFN therapy and peg-IFN plus ribavirin combination therapy. Enomoto et al. first noted that outcome of IFN therapy is related to the total number of amino Erlotinib chemical structure acid substitutions in a 40 amino acid stretch

Maraviroc concentration of the NS5A region.72,73 They designated this region the interferon sensitivity determining region (ISDR). Following this discovery, several other regions were also reported to correlate with the effect of IFN or peg-IFN plus ribavirin combination therapy. Corresponding amino acid sequences that have been reported so far are listed in Table 2. Recently, Enomoto et al. compared 88 full-length genotype 1b nucleotide sequences obtained from patients treated with peg-IFN plus ribavirin combination therapy and found that only core and ISDR amino acid substitutions are predictive of early response to therapy.108 Substitution of core protein amino acid 70 is of particular interest, not only as a predictor of effect of peg-IFN plus ribavirin combination therapy, but also because of the curious interactions between viral and host proteins as discussed below. Recently, an association between common genetic variation in the human

IL28B locus and the effect of peg-interferon and ribavirin therapy was found.135–138 The single nucleotide polymorphisms (SNPs) in the IL28B locus that are associated with SVR following combination therapy (rs8099917T and rs12979860 C) have higher allele frequencies in Asian and Caucasian populations than in African populations, in which the response to IFN is known to be relatively poorer than other ethnic groups. rs12979860 MCE公司 has also been reported to be associated with spontaneous eradication of HCV.139 Interestingly, we found that amino acid substitutions in the core region of HCV are strongly associated with IL28B SNP genotype. As shown in Fig. 4, the T allele of SNP rs8099917 within the IL28B locus is associated with core amino acid 70 arginine, which is associated with favorable response to peg-IFN plus ribavirin combination therapy.130,131 This association of human genetic variation and viral amino acid substitutions is particularly interesting. The viral strain that is relatively more sensitive to the combination therapy is more prevalent in patients that have the SNP genotype associated with a higher eradication rate of the virus by combination therapy or spontaneous elimination.

Isabel

Finegold, Milton Fingas, Christian Finn, Richard Fiorucci, Stefano Firpi, Roberto fischman, aaron Fisher, Robert Fishman, Douglas Fleming, Robert Fletcher, Linda Florman, Sander Flotte, Terence Angiogenesis inhibitor Fontana, Robert Forbes, Stuart Forner, Alejandro Forns, Xavier Foster, Graham Foster, Temitope Foung, Steven Franken, Sebastian Freedman, Neal Freeman, Michael Freeman, Richard French, Barbara Fried, Michael Friedman, Joshua Friedman, Scott Furth, Mark Gale, Michael Galle, Peter Galun, Eithan Gandhi, Chandrashekhar Gane, Edward Ganger, Daniel R. Gant, Timothy W. Gao, Bin García-Buey, Luisa Garcia-Pagan, Juan Carlos Gasser, Robin Gastaldelli, Amalia Gastaminza, Pablo Gaudio, Eugenio Gawrieh, Samer Geier, Andreas Geisler, Fabian Geller, David Genesca, Joan George, Jacob Gerlach, Jörg Gershwin, M. Eric Ghany, Marc Ghosh, Sagarmoy Giannelli, Gianluigi Gilbert, Richard Gilgenkrantz, Helene Ginsberg, Henry N. Glaser,

Shannon Gleeson, Dermot Gluud, Christian Goessling, Wolfram Goldberg, David Goldin, Robert Goldman, Radoslav Gong, Zhiyuan Gonzales, Emmanuel Gonzalez, Frank Gonzalez, Stevan Gordon, Stuart Doramapimod molecular weight C. Gordon-Walker, Timothy Gorham, James Görlach, Agnes Götte, Matthias Gottesman, Michael Grace, Norman Gradilone,

Sergio Grakoui, Arash Gramantieri, Laura Graziadei, Ivo Grebely, Jason Green, Richard Greenbaum, Linda Gressner, Olav Gretch, David Grewal, Priya Groen, Albert Grompe, Markus Groszmann, Roberto Guan, Xin-Yuan Guevara, Monica Guha, Indra Neil Guinness, Lorna Gülberg, Veit Guo, Grace Gupta, Nitika Gupta, Sanjeev Gust, Ian D. Haber, Barbara A. Hagenbuch, Bruno Hall, Angela Halsted, Charles Haluska, Paul Hampe, Jochen Han, Kwang Hyub Han, Steven-Huy Harnois, Denise Harrell, Laura Harrison, M. Harrison, Stephen Harzke, Amy Hasegawa, minoru Hassan, Manal Hawke, Roy Hay, David Hay, J. Eileen Hayashi, Paul Haybaeck, medchemexpress Johannes He, Ruth He, YouWen Heathcote, E. Jenny Heim, Markus Heimbach, Julie Henderson, Neil Herrera, Jorge Herzog, Roland Heuman, Douglas Hilgard, Philip Hinson, Jack A. Hirschfield, Gideon Hoek, Jan Hofer, Aldebaran Hoffman, Brad Hofker, Marten Hofmann, Alan Hogaboam, Cory Hollinger, F. Blaine Holmberg, Scott Honda, Masao Hoofnagle, Jay Horton, Jay Hoshida, Yujin Hotta, Hak Houchen, Courtney Hsieh, Shie-Liang Hsu, Chiun Huang, Henry Huang, Wendong Hubscher, Stefan Huebert, Robert hughes, Jeremy Hui, Lijian Huppert, Stacey Hussain, H.

Several hypotheses have been proposed to explain the etiology of adipose tissue dysfunction in obesity.25-30 A genetic link to adipose tissue IR is suggested by the observation that nonobese subjects with a strong family history of T2DM already

have early defects in adipose tissue function,25, 31 although these studies have not focused on the effect of adipose tissue on hepatic steatosis. Although MHO subjects had a much worse BMI, their metabolic profile was similar to that of lean insulin-sensitive subjects. LBH589 purchase However, it was not completely normal because there was already a trend toward worsening hepatic insulin sensitivity (Table 1) and a significant reduction in plasma adiponectin, insulin suppression of plasma FFA, and established muscle insulin resistance (Fig. 4B). Nevertheless, this reduction was not as severe as in Q1. Patients in Q1 already had significant signs of metabolic distress with higher AST/ALT (Fig. 2), dyslipidemia (i.e., high TG/low HDL-C) (Fig. 3), liver and muscle IR (Fig. 4), hepatic steatosis (Table 2) and NASH (Fig. 6). Of note, visceral fat was not different across quartiles and failed to explain the Sirolimus price metabolic and histological differences. This is consistent with recent work suggesting that hepatic fat is more closely associated with the metabolic abnormalities in NAFLD than visceral fat.32 Though the metabolic disturbances described here

cannot be entirely ascribed to dysfunctional adipose tissue, their strong association with dysfunctional fat suggests an important role in the pathogenesis of metabolic/histological defects in NAFLD. It also suggests that lipotoxicity has a low threshold in NAFLD and that its impact varies among target tissues. Skeletal muscle appeared rapidly affected by dysfunctional adipose tissue (Q1-Q3), whereas it was more gradual at the level of the liver (Fig. 4). However, at the extreme

of adipose tissue IR (Q4), all metabolic variables (i.e., AST/ALT, TG/HDL-C, and hepatic/muscle IR) further deteriorated, suggesting that target tissues continue to be affected and susceptible to worsening lipotoxicity. This has clinical implications for lipotoxicity in the development and treatment of steatohepatitis and fibrosis. The lack of an association between an exacerbation medchemexpress of adipose tissue IR and steatohepatitis (Fig. 6) does not mean that, upon reversal of adipose tissue IR with a TZD, there cannot be a marked improvement in steatohepatitis, as previously reported.9 Indeed, the low threshold for steatohepatitis (already observed in Q1) would suggest that even modest reversal of adipose tissue IR may be beneficial in NASH. In our hands, reversal of adipose tissue IR by a TZD had the closest correlation with necroinflammation (r = 0.47, P < 0.01), but also was associated with changes in steatosis (r = 0.29; P = 0.049) and, to a lesser degree, fibrosis (0.

Several hypotheses have been proposed to explain the etiology of adipose tissue dysfunction in obesity.25-30 A genetic link to adipose tissue IR is suggested by the observation that nonobese subjects with a strong family history of T2DM already

have early defects in adipose tissue function,25, 31 although these studies have not focused on the effect of adipose tissue on hepatic steatosis. Although MHO subjects had a much worse BMI, their metabolic profile was similar to that of lean insulin-sensitive subjects. AZD4547 price However, it was not completely normal because there was already a trend toward worsening hepatic insulin sensitivity (Table 1) and a significant reduction in plasma adiponectin, insulin suppression of plasma FFA, and established muscle insulin resistance (Fig. 4B). Nevertheless, this reduction was not as severe as in Q1. Patients in Q1 already had significant signs of metabolic distress with higher AST/ALT (Fig. 2), dyslipidemia (i.e., high TG/low HDL-C) (Fig. 3), liver and muscle IR (Fig. 4), hepatic steatosis (Table 2) and NASH (Fig. 6). Of note, visceral fat was not different across quartiles and failed to explain the see more metabolic and histological differences. This is consistent with recent work suggesting that hepatic fat is more closely associated with the metabolic abnormalities in NAFLD than visceral fat.32 Though the metabolic disturbances described here

cannot be entirely ascribed to dysfunctional adipose tissue, their strong association with dysfunctional fat suggests an important role in the pathogenesis of metabolic/histological defects in NAFLD. It also suggests that lipotoxicity has a low threshold in NAFLD and that its impact varies among target tissues. Skeletal muscle appeared rapidly affected by dysfunctional adipose tissue (Q1-Q3), whereas it was more gradual at the level of the liver (Fig. 4). However, at the extreme

of adipose tissue IR (Q4), all metabolic variables (i.e., AST/ALT, TG/HDL-C, and hepatic/muscle IR) further deteriorated, suggesting that target tissues continue to be affected and susceptible to worsening lipotoxicity. This has clinical implications for lipotoxicity in the development and treatment of steatohepatitis and fibrosis. The lack of an association between an exacerbation 上海皓元 of adipose tissue IR and steatohepatitis (Fig. 6) does not mean that, upon reversal of adipose tissue IR with a TZD, there cannot be a marked improvement in steatohepatitis, as previously reported.9 Indeed, the low threshold for steatohepatitis (already observed in Q1) would suggest that even modest reversal of adipose tissue IR may be beneficial in NASH. In our hands, reversal of adipose tissue IR by a TZD had the closest correlation with necroinflammation (r = 0.47, P < 0.01), but also was associated with changes in steatosis (r = 0.29; P = 0.049) and, to a lesser degree, fibrosis (0.

Several hypotheses have been proposed to explain the etiology of adipose tissue dysfunction in obesity.25-30 A genetic link to adipose tissue IR is suggested by the observation that nonobese subjects with a strong family history of T2DM already

have early defects in adipose tissue function,25, 31 although these studies have not focused on the effect of adipose tissue on hepatic steatosis. Although MHO subjects had a much worse BMI, their metabolic profile was similar to that of lean insulin-sensitive subjects. R788 purchase However, it was not completely normal because there was already a trend toward worsening hepatic insulin sensitivity (Table 1) and a significant reduction in plasma adiponectin, insulin suppression of plasma FFA, and established muscle insulin resistance (Fig. 4B). Nevertheless, this reduction was not as severe as in Q1. Patients in Q1 already had significant signs of metabolic distress with higher AST/ALT (Fig. 2), dyslipidemia (i.e., high TG/low HDL-C) (Fig. 3), liver and muscle IR (Fig. 4), hepatic steatosis (Table 2) and NASH (Fig. 6). Of note, visceral fat was not different across quartiles and failed to explain the Ruxolitinib metabolic and histological differences. This is consistent with recent work suggesting that hepatic fat is more closely associated with the metabolic abnormalities in NAFLD than visceral fat.32 Though the metabolic disturbances described here

cannot be entirely ascribed to dysfunctional adipose tissue, their strong association with dysfunctional fat suggests an important role in the pathogenesis of metabolic/histological defects in NAFLD. It also suggests that lipotoxicity has a low threshold in NAFLD and that its impact varies among target tissues. Skeletal muscle appeared rapidly affected by dysfunctional adipose tissue (Q1-Q3), whereas it was more gradual at the level of the liver (Fig. 4). However, at the extreme

of adipose tissue IR (Q4), all metabolic variables (i.e., AST/ALT, TG/HDL-C, and hepatic/muscle IR) further deteriorated, suggesting that target tissues continue to be affected and susceptible to worsening lipotoxicity. This has clinical implications for lipotoxicity in the development and treatment of steatohepatitis and fibrosis. The lack of an association between an exacerbation 上海皓元医药股份有限公司 of adipose tissue IR and steatohepatitis (Fig. 6) does not mean that, upon reversal of adipose tissue IR with a TZD, there cannot be a marked improvement in steatohepatitis, as previously reported.9 Indeed, the low threshold for steatohepatitis (already observed in Q1) would suggest that even modest reversal of adipose tissue IR may be beneficial in NASH. In our hands, reversal of adipose tissue IR by a TZD had the closest correlation with necroinflammation (r = 0.47, P < 0.01), but also was associated with changes in steatosis (r = 0.29; P = 0.049) and, to a lesser degree, fibrosis (0.