bluuebunny/crossref_metadata_2025_split huggingface dataset:
1860-P: Liver Fat and Visceral Fat Are Associated with Different Metabolic and Pathophysiologic Profiles but with Similar Relationships with Whole Body Insulin Resistance
Authors: PARK IE BYUNG , LEE KIYOUNG , LEE DAEHO 
Published: June 2019

MRI-based examinations of hepatic steatosis and body fat are becoming more familiar and useful for metabolic studies including NAFLD. MRI-estimated proton density fat fraction (MRI-PDFF) can haptic fat exactly without biopsy, enabling us to evaluate the effect of liver fat more sophisticatedly than ever. Although hepatic fat and visceral fats are both important for metabolic and cardiovascular diseases, detailed evaluation of the effect of each fat depot on various metabolic profiles have not been performed, In the present study, we evaluated the differential effect between hepatic and visceral fats on various metabolic profiles including glucose and lipid metabolism, islet cell function, insulin resistance, and inflammation. A total of 82 subjects (25 healthy volunteers and 57 patients with suspected, or proven NAFLD) who underwent MRI examinations for MRI-PDFF and visceral fat measurement. Additionally, anthropometric and laboratory studies and total body fat measurement by DXA were also performed. Other causes of chronic liver diseases, such as alcoholic, autoimmune or viral hepatitis, and other diseases, were excluded from the study. The amounts of hepatic fat and visceral fats measured by MRI showed similar significant correlations with HOMA-IR (r=0.540 vs. r=0.538, p &lt;0.01, respectively) as with A1C (r=0.448 vs. r=0.495, p &lt;0.01 each). However, hepatic fat showed more close association with FBS, triacylglycerol, complement factor C3, and cytokeratin 18. Visceral fat correlated more with fasting plasma insulin, glucagon and angiotensinogen levels. Total body fat measured by DXA did not show such characteristic patterns of correlations and showed only a weak or no correlation with those parameters. Thus, our results showed that both hepatic fat and visceral fat depots are important determinants of whole-body insulin resistance and glucose metabolism.

Disclosure
I. Park: None. K. Lee: None. D. Lee: None.
1863-P: The Hepatic Role of Heat Shock Protein 72 in the Pathogenesis of Type 2 Diabetes
Authors: KONDO TATSUYA , KITANO SAYAKA , MIYAKAWA NOBUKAZU , WATANABE TAKURO , GOTO RIEKO , ONO KAORU , IGATA MOTOYUKI , KAWASHIMA JUNJI , MOTOSHIMA HIROYUKI , MATSUMURA TAKESHI , ARAKI EIICHI 
Published: June 2019

Cell stresses, such as ER stress or oxidative stress are considered to be key mediators in pathophysiology of type 2 diabetes. Heat shock protein (HSP) 72, a major inducible HSP against heat, serves to protect cells from those cellular stresses and works in protein quality control. Induction of HSP72 improves glucose intolerance in type 2 diabetic model mice. In this study, we investigated glucose metabolism in whole body HSP72 deficient (KO) mice. The effects of hepatic HSP72 induction in KO mice were also investigated. KO mice and control mice were subjected to a high-fat diet regimen. Metabolic parameters and pathophysiological examination were performed. HSP72 was overexpressed in mice by lenti-virus to investigate the role of HSP72 in liver. There were no significant differences in body weight and food intake between two groups. Fasting and random-fed blood glucose levels were significantly higher in KO mice than those in control mice. The fasting insulin level was significantly lower in KO mice. Upon glucose challenge, blood glucose levels were higher in KO mice. On insulin tolerance test, KO mice exhibited insulin resistant phenotype. Visceral fat mass was increased and hepatic steatosis was obvious in KO mice with increased SREBP-1c mRNA expression. Upon insulin stimulation, phosphorylation of Akt was decreased in KO liver, with increased activation of JNK. Hepatic gluconeogenesis was not suppressed in KO accompanied by increased gluconeogenic enzymes. When restoring HSP72 expression in liver by lenti-virus on KO mice, blood glucose, hepatic steatosis and gluconeogenesis were ameliorated. Interestingly, visceral fat size and macrophage infiltration were both reversed by hepatic HSP72 induction. Deficiency of HSP72 leads to type 2 diabetic phenotype. As induction of HSP72 in liver is beneficial to improve glucose homeostasis in KO, the abundance of HSP72 in liver is critical in diabetic pathophysiology, and appropriate HSP72 induction may serve as a target in the treatment of type 2 diabetes.

Disclosure
T. Kondo: None. S. Kitano: None. N. Miyakawa: None. T. Watanabe: None. R. Goto: None. K. Ono: None. M. Igata: None. J. Kawashima: None. H. Motoshima: None. T. Matsumura: None. E. Araki: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Novo Nordisk Inc., Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; Astellas Pharma Inc., Merck & Co., Inc., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi.

Funding
Japan Society for the Promotion of Science
1868-P: Bromocriptine (BC) Improves Hepatic Steatosis, Inflammation, and ER Stress in a Mouse Obesogenic Dietary Model of Nonalcoholic Steatohepatitis (NASH)
Authors: TSAI TSUNG-HUANG , CINCOTTA ANTHONY 
Published: June 2019

The pathogenesis of NASH is a complex interaction among hepatic lipotoxicity, oxidative stress, mitochondrial dysfunction and ER stress leading to hepatic inflammation, cell death, and fibrosis. Bromocriptine, a dopamine D2 receptor agonist is known to reduce adipose lipolysis, plasma hyperFFAemia, and hepatic lipogenesis and inflammation. Also, the antidiabetes drug, bromocriptine-QR has been demonstrated to reduce cardiovascular events. Therefore, we investigated the impact of BC on hepatic pathophysiology in a mouse obesogenic dietary model of NASH. Six-week-old C57B6 male mice (N=8/gr) were maintained on a 40 kcal% fat diet with 5% fructose in the drinking water for 12 weeks to induce NASH then randomized to BC (10mg/kg) or vehicle daily treatment for an additional 3 weeks while maintained on the diet. A group of mice on normal diet was used as a normal reference control. Such BC therapy reduced plasma glucose (28.6%), insulin (31.4%), leptin (42.7%), cholesterol (21.9%) and body weight (14.2%) relative to vehicle (P&lt;0.01). Also, plasma biomarkers of hepatic inflammation: elevated ALT, AST, and LPS, were reduced by BC (32.6, 38.8, and 38.1%, respectively, P&lt;0.05) vs. vehicle. Treatment with BC significantly reduced four gene expression markers each for steatosis (SREBP1c, FASN, ACC1, PLIN2), fatty acid oxidation (PPARα, PGC1α, CPT1, UCP1), inflammation (TNFa, IL1β, MCP1, iNOS), ER stress (DDIT3, ATF, sXBP1, HSPA5), and fibrosis (αSMA, TGFβ, COL1A, TXNIP) by 16-76, 17-47, 31-75, 20-55, and 21-70%, respectively (P&lt;0.05 for each gene). Finally, histological analysis of the liver revealed BC therapy reduced steatosis, inflammation, and ballooning degeneration resulting in a 63% reduced NAFLD activity score (2.6 vs. 7.1, P&lt;0.01). The BC effects on NASH resulted in hepatic physiology closely resembling the normal diet control group. These results suggest that BC could be an effective therapy for NAFLD and NASH.

Disclosure
T. Tsai: Employee; Self; VeroScience LLC. A. Cincotta: Employee; Self; VeroScience LLC.
1870-P: Glucagon-Receptor Signaling Reverses Hepatic Steatosis Independent of Leptin Receptor Expression
Authors: NASON SHELLY , KIM TEAYOUN , ANTIPENKO JESSICA P. , FINAN BRIAN , DIMARCHI RICHARD , HABEGGER KIRK M. 
Published: June 2019

Glucagon is an essential regulator of glucose and lipid metabolism that also promotes weight loss. We have shown that GCGR signaling increases fatty acid oxidation (FAOx) in primary hepatocytes and reduces liver triglycerides in DIO mice; however, the mechanisms underlying this aspect of glucagon biology remains unclear. Investigation of downstream GCGR targets elucidated potent and previously unknown regulation of liver leptin receptor (Lepr) expression. Intriguingly, we found GCGR agonism induces hepatic Lepr expression in vivo and in vitro. Liver leptin signaling is known to increase FAOx and decrease liver triglycerides, similar to glucagon action. Therefore, we hypothesized that glucagon increases hepatic LEPR, which is necessary for glucagon-mediated reversal of hepatic steatosis. Administration of the selective GCGR agonist IUB288 in both lean and diet-induced obese (DIO) mice increases both total hepatic Lepr (p&lt;0.001) expression and the signaling isoform Lepr-b (p&lt;0.05) in acute and chronic settings. In addition, Lepr-b increased in IUB288 treated primary hepatocytes (p&lt;0.05), suggesting cell-autonomous regulation. Further, GCGR activation potentiates leptin-stimulated phosphorylation of AMPK (Thr172) in a dose-dependent manner, suggesting an increase in hepatic leptin sensitivity. Mice deficient for the hepatic leptin receptor (LeprΔliver) displayed increased hepatic triglycerides on a chow diet alone (p&lt;0.001), which persisted in a DIO state, with no differences in body weight or composition. Surprisingly, chronic administration of IUB288 in DIO WT and LeprΔliver mice resulted in similar reductions of liver triglycerides. Glucagon also reduces plasma lipids during oral lipid challenge. Similar to liver triglycerides, there were no differences in response to IUB288 between WT and LeprΔliver mice. Together these data suggest that although hepatic glucagon and leptin signaling have similar lipid targets, these appear to be two distinct pathways.

Disclosure
S. Nason: None. T. Kim: None. J.P. Antipenko: None. B. Finan: Employee; Self; Novo Nordisk A/S. R. DiMarchi: Employee; Self; Novo Nordisk Inc. K.M. Habegger: Consultant; Self; Glyscend, Inc., Novo Nordisk Inc. Research Support; Self; Glyscend, Inc. Stock/Shareholder; Self; Glyscend, Inc.

Funding
National Institutes of Health (T32HL1053491, R011DK112934-01)
1874-P: A Novel Role for SerpinB1 in the Regulation of Insulin Signaling in Hepatocytes
Authors: ORIME KAZUKI , DE JESUS DARIO F. , JHALA ULUPI , KULKARNI ROHIT 
Published: June 2019

Compensatory expansion of β cell mass has been pursued as a potential therapeutic strategy to cure diabetes. We previously identified SerpinB1 as a hepatocyte-derived circulating factor that contributes to adaptive beta cell expansion in the liver-specific insulin receptor knockout (LIRKO) mouse. To understand how SerpinB1 is regulated and secreted, we began by first investigating the mechanism(s) and signaling pathways that modulate the gene and protein expression of SerpinB1 in hepatocytes. Hepatic SerpinB1 expression was elevated in insulin resistant mouse models such as db/db and ob/ob, and circulating interleukin-6 (IL-6) levels were higher in these mice. Indeed, IL-6 induced SerpinB1 expression in HepG2 cells and human primary hepatocytes via the JAK/STAT3 pathway, indicating an important role for this cytokine in inducing the expression of the protease inhibitor in insulin resistant states. Conversely, silencing of SERPINB1 gene in hepatocytes decreased INSR gene and protein expression with a consequent alteration of expression of several downstream signaling genes related to gluconeogenesis and cell proliferation in hepatocytes. Ribosomal protein S3 (RPS3), identified as a binding partner of SerpinB1 in HepG2 cells, exhibited reduced expression in db/db and ob/ob mice liver along with reduced insulin receptor (IR) expression. Silencing of RPS3 gene in HepG2 cells, phenocopied the effects of SerpinB1 gene silencing, and decreased IR protein expression with consequent alterations in downstream signaling proteins. Additional studies are required to examine the precise regulation of IR expression by SerpinB1 and how the latter is secreted from insulin resistant hepatocytes. These results indicate that SerpinB1 expression is upregulated in insulin resistance by IL-6 and the SerpinB1/RPS3 complex plays a role in regulating insulin signaling in hepatocytes.

Disclosure
K. Orime: None. D.F. De Jesus: None. U. Jhala: None. R. Kulkarni: None.
1880-P: The Protein-Tyrosine Phosphatase Shp1 Interacts with PPAR Gamma and Regulates Its Transcriptional Activity through Dephosphorylation of Selected Tyrosine Sites
Authors: KUMAR AMIT , LAVALLEE-BOURGET MARIE-HELENE , FOREST MARIE-PIER , SCHWAB MICHAEL , BELLMANN KERSTIN , HOUDE VANESSA , MAAROUFI HALIM , BEAUCHEMIN NICOLE , MARETTE ANDRE 
Published: June 2019

Src homology region 2 domain-containing phosphatase-1 (Shp1) plays an important role in modulating insulin signaling and thereby glucose homeostasis. Our laboratory has demonstrated that despite being more prone to hepatic steatosis, mice with a liver specific Shp1 knock out (Shp1H-KO) on high-fat diet (HFD) exhibit improved fasting glycaemia, reduced insulin resistance and lower inflammation than their flox/flox littermates. Microarray analysis of HFD-fed Shp1H-KO versus Shp1fl/fl livers revealed elevated levels of peroxisome proliferator-activated receptor gamma (PPARγ), an important transcription factor controlling adipogenesis. In addition, overexpression of Shp1 decreased PPARγ activity in vitro. The aim of this study was to investigate the mechanism of regulation of PPARγ by Shp1. Molecular modeling analyses suggested that Shp1 interaction with PPARγ depends on the tyrosine phosphorylation status of PPARγ. We found, by co-immunoprecipitation, that Shp1 N-terminal SH2-domains binds to PPARγ. We confirmed PPARγ tyrosine-phosphorylation and demonstrated that this phosphorylation could be reduced by Shp1 in vitro. Using mass spectrometry, we identified 5 phosphorylated tyrosine residues in PPARγ. Mutagenesis experiments showed that PPARγ significantly lost its activity when two of these sites were selectively and independently mutated to the non-phosphorylatable phenylalanine but did not interfere with the nuclear localization of PPARγ. Additionally, we generated Shp1 knockout HepG2 cells using CRISPR-Cas9 technology. We found that expression of several PPARγ regulated transcripts was upregulated in Shp1-KO cells as compared to control cells. Altogether, we show that PPARγ is a novel substrate of Shp1. Our results reveal a fine regulation of PPARγ tyrosine phosphorylation by Shp1, which might lead to novel therapeutic approaches for treating metabolic disorders related to obesity.

Disclosure
A. Kumar: None. M. Lavallee-Bourget: None. M. Forest: None. M. Schwab: None. K. Bellmann: None. V. Houde: None. H. Maaroufi: None. N. Beauchemin: None. A. Marette: Advisory Panel; Self; Plexus, Valbiotis. Consultant; Self; Danone Nutricia Research.
1884-P: Serum ANGPTL2, ANGPTL3, and ANGPTL4 as Potential Biomarkers for Diagnosis of Nonalcoholic Fatty Liver Disease
Authors: MA YAN , WANG YAN , WANG XIN , YANG LONGYAN , LANG JIANAN , ZHAO DONG 
Published: June 2019

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease that seriously affects public health around the world. We investigate the circulating levels of ANGPTL2, ANGPTL3 and ANGPTL4, and detects the correlation with metabolic and biochemical parameters, then examines the efficacy of ANGPTLs for the assessment of NAFLD. Serum levels of ANGPTL2, ANGPTL3, ANGPTL4 and ANGPTL6 in NAFLD patients (n=52) and non NAFLD subjects (n=52) were quantified by ELISA. Then we further evaluated the utility of ANGPTLs as biomarkers for predicting NAFLD by employing receiver operating characteristic (ROC) analysis. Our data demonstrate that (1) serum levels of ANGPTL2 and ANGPTL4 increased, ANGPTL3 level decreased along with the transition from no NAFLD to NAFLD and from mild NAFLD to moderate-to-severe NAFLD patients. However, ANGPTL6 level unchanged altered among these stages; (2) Pearson association analysis demonstrated that ANGPTL2 levels were positively correlated with ALT, AST and GGT; but ANGPTL3 levels were negatively associated with ALT and GGT; ANGPTL4 levels were positively correlated with ALT, AST and GGT; (3) The area under the ROC curve (AUC) for ANGPTL2, ANGPTL3 and ANGPTL4 were 0.647, 0.746 and 0.666; When the three factors were jointly analyzed, the area under the ROC curve was 0.778, exhibiting the strongest capability in predicting diagnosis in NAFLD patients; (4) The changes of serum ANGPTL2 and ANGPTL3 in NAFLD patients may be due to the changed expression in liver tissues of NAFLD patients; (5) Gene enrichment analysis results show a positive correlation between ANGPTL2 level and the activation of NF-κB signaling in NAFLD samples, and a negative correlation between ANGPTL3 level and the activation of JNK signaling in NAFLD samples. Taken together, ANGPTL2, ANGPTL3 and ANGPTL4 levels might be new and important predictors of the severity of NAFLD.

Disclosure
Y. Ma: None. Y. Wang: None. X. Wang: None. L. Yang: None. J. Lang: None. D. Zhao: None.

Funding
National Natural Science Foundation of China; National Science Funding in China
19-OR: Controlled-Release Mitochondrial Protonophore (CRMP) Reverses Hypertriglyceridemia and Hepatic Steatosis in Dysmetabolic Nonhuman Primates
Authors: GOEDEKE LEIGH , ROMERAL VALLE MONTALVO , BUTRICO GINA MARIE , KAHN MARIO , DUFOUR SYLVIE , ZHANG XIAN-MAN , CLINE GARY , PETERSEN KITT , CHNG KEEFE , SHULMAN GERALD I. 
Published: June 2019

NAFLD is estimated to affect up to one third of the general population and is a major predisposing factor in the pathogenesis of hepatic insulin resistance, NASH, and T2D. While weight loss is highly effective at reversing NAFLD, insulin resistance and T2D, it is difficult to sustain and new therapies are required. Our lab has recently developed a controlled-release mitochondrial protonophore (CRMP) that is functionally liver-targeted and promotes oxidation of hepatic triglycerides by promoting a subtle sustained increase in hepatic mitochondrial inefficiency. While we have previously demonstrated that CRMP safely reverses hypertriglyceridemia, fatty liver, and hepatic inflammation/fibrosis in diet-induced rodent models of obesity, there remains a critical need to assess the safety and efficacy in a model highly relevant to humans. Here, we evaluated the impact of CRMP treatment on hepatic mitochondrial oxidation and the reversal of hypertriglyceridemia, NAFLD, and insulin resistance in a spontaneous nonhuman primate model of NAFLD and the metabolic syndrome. Using Positional Isotopomer NMR Tracer Analysis (PINTA), we demonstrate that acute CRMP treatment (single dose of 5 mg/kg) significantly increases rates of hepatic mitochondrial fat oxidation by 40% (P&lt;0.05). Importantly, CRMP treatment (5 mg/kg/day x 6 weeks) reduced hepatic and plasma triglycerides by 20% (both P=0.05) independently of changes in body weight, food intake, body temperature or adverse reactions. Furthermore, administration of CRMP significantly reduced endogenous glucose production by 18% (P&lt;0.05), which could be attributed to a ~20% reduction in hepatic acetyl-CoA content (as assessed by whole-body βOHB turnover) and pyruvate carboxylase flux.
Conclusion: These studies provide important proof-of-concept data to support the development of novel liver-targeted mitochondrial uncouplers for the treatment of NAFLD/NASH and T2D in humans.

Disclosure
L. Goedeke: None. V. Montalvo Romeral: None. G. Butrico: None. M. Kahn: None. S. Dufour: None. X. Zhang: None. G. Cline: None. K. Petersen: Advisory Panel; Spouse/Partner; Aegerion Pharmaceuticals, AstraZeneca, AstraZeneca, Janssen Research & Development, Merck & Co., Inc., Novo Nordisk A/S. Consultant; Spouse/Partner; Gilead Sciences, Inc. Consultant; Self; Merck & Co., Inc. Consultant; Spouse/Partner; Nimbus Discoverey. Consultant; Self; Novo Nordisk A/S. K. Chng: None. G.I. Shulman: Advisory Panel; Self; AstraZeneca, Janssen Research & Development, Merck & Co., Inc. Advisory Panel; Spouse/Partner; Merck & Co., Inc. Board Member; Self; Novo Nordisk A/S. Consultant; Self; Aegerion Pharmaceuticals, IMetabolic BioPharma Corporation, Longitude Capital, Nimbus Discovery, Inc., Staten Biotechnology B.V.

Funding
National Institutes of Health
190-OR: Weight-Loss after Exercise Increases Non-Insulin-Dependent Glucose Clearance in Adults with Metabolic Syndrome
Authors: HARI ADITHYA , AXELROD CHRISTOPHER L. , MEY JACOB T. , KIRWAN JOHN P. 
Published: June 2019

Fasting plasma glucose is a composite measure of hepatic glucose production (HGP) and non-insulin-dependent (basal) tissue glucose clearance rate (bGCR). A rise in fasting plasma glucose, within the nondiabetic range, is purported to be regulated by decreased bGCR rather than increased HGP. However, the role of bGCR in improving metabolic syndrome (MetS) is not yet fully understood. We sought to explore the novel impact of weight loss induced by exercise on bGCR in individuals with MetS. Fourteen sedentary adults with MetS (9 females, 68 years, 35.2 kg/m2) participated in a 12-week moderate intensity exercise program (~65% VO2max, 1 hr/day, 5 days/week). MetS was defined using ATP III guidelines. Insulin resistance (IR) was estimated using a hyperinsulinemic (40 mU/m2/min) euglycemic (90 mg/dL) clamp. Rate of glucose disappearance (Rd) was determined using [6,6-2H2]-glucose during fasting and insulin stimulation. GCR was calculated as Rd relative to the prevailing glucose concentration. At baseline, bGCR correlated with IR and adiponectin (r=0.69 and 0.68, P&lt;0.01). Following exercise training and relative to pre-intervention: (i) body weight, VO2max and IR improved (6.6, 17 and 7.7%, respectively; P&lt;0.05); (ii) cardiometabolic risk factors decreased (Triglycerides: 30%; Total Cholesterol: 15%; LDL: 15%; sBP: 11% and dBP: 14.5%; all P&lt;0.05); (iii) fasting glucose and insulin concentration decreased (6% and 32%, P&lt;0.05), and bGCR increased (~1.5 fold, P&lt;0.01). The increase in bGCR correlated positively with changes in body weight, fat mass, suppression of HGP during the clamp, and serum triglycerides (r=0.5, 0.49, 0.61 and 0.62, respectively; P&lt;0.05). Weight loss following aerobic exercise training breaks the vicious cycle of increased insulin resistance and secretion by increasing the contribution of bGCR to fasting glycemia. This evidences the unique and multifactorial benefits of exercise concomitant with weight loss in mediating cardiometabolic risk.

Disclosure
A. Hari: None. C.L. Axelrod: None. J.T. Mey: None. J.P. Kirwan: None.

Funding
National Institutes of Health; National Center for Research Resources