bluuebunny/crossref_metadata_2025_split huggingface dataset:
1817-P: Elafibranor and Glucagon-Like Peptide-1 Receptor Agonists Synergize to Attenuate Hepatic Inflammation and Fibrosis in a Rodent Model of Obesity, Insulin Resistance, and NASH
Authors: LEGRY VANESSA , DESCAMPS EMELINE , DEBAECKER SIMON , STANKOVIC-VALENTIN NICOLAS , PARROCHE PEGGY , DEGALLAIX NATHALIE , POULAIN PHILIPPE , STAELS BART , WALCZAK ROBERT 
Published: June 2020

Elafibranor and GLP-1 receptor agonists synergize to attenuate hepatic inflammation and fibrosis in a rodent model of obesity, insulin resistance and NASH.
Liver steatosis contributes to the development of hepatic insulin resistance and is present in the majority of T2DM patients, who are 50 or older. Therefore, many NAFLD patients with diabetes are currently treated with the antidiabetics, including GLP-1 receptor agonists (GLP-1RA). Elafibranor (ELA), a phase 3 candidate for the treatment of NASH, ameliorates insulin sensitivity and lowers HbA1c in patients with NASH-associated T2DM.
The aim of our study was to evaluate the pharmacological benefit of combining GLP-1RA and ELA in the context of NASH-associated insulin resistance.
GLP-1RA administration induced body weight loss, reduced insulinemia, HOMA-IR and liver steatosis in obese mice with NASH and insulin resistance, but its action on liver fibrosis was negligible. ELA co-administration allowed for GLP-1RA dose reduction and resolved all NASH features. Food intake was also normalized at reduced GLP-1RA doses.
Plasma CRP concentration was reduced by 56% in mice that received the combination treatment. Transcriptomic analyses revealed that the synergism between ELA and GLP-1RA in the liver was limited to the modulation of the inflammatory pathways with no effect on metabolic genes. Since ELA and GLP-1RA also synergize in vitro to reduce TNFa secretion in LPS-activated THP1 macrophages, we postulate that both drugs have a direct action on inflammatory cells in the liver. Further analyses to characterize ELA and GLP-1RA effects on innate and adaptive immune responses will be presented.
Conclusion: ELA and GLP-1RA synergize to reduce hepatic inflammation and fibrosis in a model of NASH and obesity. These results suggest a potential therapeutic interest of combining ELA and GLP-1RA for the treatment of T2DM in NASH patients.

Disclosure
V. Legry: Employee; Self; GENFIT. Stock/Shareholder; Self; GENFIT. E. Descamps: Employee; Self; GENFIT. Employee; Spouse/Partner; GENFIT. Stock/Shareholder; Spouse/Partner; GENFIT. Stock/Shareholder; Self; GENFIT. S. Debaecker: Employee; Self; GENFIT. Stock/Shareholder; Self; GENFIT. N. Stankovic-Valentin: Employee; Self; GENFIT. Stock/Shareholder; Self; GENFIT. P. Parroche: Employee; Self; GENFIT. Stock/Shareholder; Self; GENFIT. N. Degallaix: Employee; Self; GENFIT. Stock/Shareholder; Self; GENFIT. P. Poulain: Employee; Self; GENFIT. Stock/Shareholder; Self; GENFIT. B. Staels: Consultant; Self; Genfit. R. Walczak: Employee; Self; GENFIT. Stock/Shareholder; Self; GENFIT.
1819-P: Gut Microbiota and PNPLA3 RS738409 Associated with Nonalcoholic Fatty Liver Disease in Obese Youth
Authors: KRAVETZ AYESHA MONGA , TESTERMAN TODD , GALUPPO BRITTANY , GRAF JOERG , SIEBEL STEPHAN , FEINN RICHARD , SANTORO NICOLA 
Published: June 2020

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver disease. Since gut microbiota has been associated with pediatric obesity, we explored the potential relationship between gut microbiota and NAFLD in obese youth, while considering the role of PNPLA3 rs738409, a genetic contributor to NAFLD. Seventy-three obese youth (BMI &gt; 95th percentile) underwent an MRI to measure hepatic fat fraction (HFF), an oral glucose tolerance test, and fasting blood sample collection. PNPLA3 rs738409 was assessed by automatic sequencing. A stool sample from each subject was collected to analyze the V4 region of the 16S rRNA gene and characterize intestinal bacteria. Shannon-Wiener index values were calculated for all samples and were compared between participants without NAFLD (HFF &lt; 5.5%; n= 29) and with NAFLD (HFF ≥ 5.5%; n= 44). We observed that subjects with NAFLD had decreased (p=0.013) bacterial diversity compared to those without NAFLD. When comparing the abundance of each bacterial phylum (n=8) and genus (n=51) between the two groups, we observed a higher Firmicutes to Bacteroidetes (F/B) ratio (p=0.019) and lower abundance of Bacteroidetes (p=0.010), Prevotella (p=0.019), Gemmiger (p=0.003), and Oscillospira (p=0.036) in those with NAFLD, compared to those without NAFLD. Multiple linear regression was conducted to determine if each phylum and genus that was different (p&lt;0.05) in abundance between the two groups was found to be predictive of HFF, while controlling for PNPLA3 genotype, race, and BMI z-score. Regression results showed that F/B ratio, Bacteroidetes, Gemmiger, and Oscillospira were associated with HFF when controlling for group variations. We also observed an additive effect of PNPLA3 rs738409 and Gemmiger, and PNPLA3 rs738409 and Oscillospira on HFF. We demonstrate that obese youth with NAFLD have different gut microbiota composition than those without NAFLD and identified individual phyla and genera that are associated with intrahepatic fat content.

Disclosure
A. Monga Kravetz: None. T. Testerman: None. B. Galuppo: None. J. Graf: None. S. Siebel: None. R. Feinn: None. N. Santoro: None.

Funding
National Institutes of Health (R01DK114504)
1823-P: Bromocriptine (BC) Normalizes Elevated Expression of Liver Genes Involved in Fatty Acid Oxidation, Lipogenesis, Inflammation, and Endoplasmic Reticulum (ER) Stress and Glucose Intolerance of High-Fat/Sucrose Diet-Fed Rats
Authors: ZHANG YAHONG , EZROKHI MICHAEL , COMINOS NICHOLAS , CINCOTTA ANTHONY H. 
Published: June 2020

Consumption of the “westernized diet” (WD) of high fat and sucrose promotes the development of hepatic insulin resistance and metabolic syndrome (MS). This diet is well known to reduce brain dopamine activity and stimulate chronic over-activation of the sympathetic nervous system that potentiate liver insulin resistance by as yet unknown mechanisms. This study evaluated the effect of circadian-timed bromocriptine, a sympatholytic dopamine agonist, to reverse the adverse effects of the WD on glucose tolerance and liver expression of several genes involved in hepatic aspects of insulin sensitivity including lipid balance, inflammation and ER stress. Female Sprague-Dawley rats were maintained on a WD of high fat (40% by kcal/g) and sucrose (29% by kcal/g) for 4 weeks and then administered BC (7.5 mg/kg) or vehicle (N =10/group) at the onset of daily waking for an additional 10 weeks while maintained on WD to study end when a GTT (3g/kg glucose) was performed and 5 days later when animals were sacrificed for analyses of hepatic genes (via PCR) involved in insulin sensitivity. A regular chow fed group (N=10) served as positive control. BC treatment reduced the GTT glucose AUC by 39% vs. controls (P&lt;0.001) without change in the insulin AUC and reduced body fat level by 35% (P= 0.01) without change in feeding vs. controls. BC also reduced hepatic gene transcripts for fatty acid oxidation - PPARa and CPT1A by 35 and 48%, respectively (P&lt;0.03), for lipid synthesis - DGAT2 by 20% (P&lt;0.04), and for inflammation and ER stress - monocyte chemoattractant protein 1 and C/EBP homologous protein by 40 and 47% (P&lt;0.05), respectively, vs. controls, all to levels observed in regular chow fed rats. This study demonstrated that bromocriptine can reverse the adverse effects of WD on hepatic lipid, inflammation, and ER stress gene expression pathways that promote hepatic insulin resistance and MS.

Disclosure
Y. Zhang: Employee; Self; VeroScience LLC. M. Ezrokhi: Employee; Self; VeroScience LLC. N. Cominos: Employee; Self; VeroScience LLC. A.H. Cincotta: Employee; Self; VeroScience LLC.
1824-P: Activation of Cardiac Mitochondrial Akt1 Improved Diabetic Cardiomyopathy through Inhibition of Melatonin Degradation and Remotely Improved Liver Metabolism
Authors: TA ALBERT , CHEN YU-HAN , CHEN YUMAY , LIN HUGO Y.H. , WANG PING H. 
Published: June 2020

Insulin resistance impaired Akt1 translocation to mitochondria in myocardium and contributed to diabetic cardiomyopathy (DCM). It is unknown whether activation of mitochondrial Akt in cardiac muscle can protect against DCM. To this end, we generated an inducible heart-specific transgenic mice with a mitochondria-targeting constitutively active Akt (CAMCAKT). A high fat-high fructose (HFF) diet induced myocardial fibrosis and heart failure, but cardiomyopathy was reversed in the CAMCAKT mice, indicating a mechanistic role of mitochondrial Akt1 signaling in DCM. RNAseq analysis revealed myocardial transcriptome changes, including suppressed Col1a1 and Col3a1 expression (fibrosis markers) recapitulating the mechanism of fibrosis. Accompanying lowered GP6 expression suggested a reduction in collagen-induced platelet activation. Pathway analysis revealed significant inhibition in multiple steps of melatonin degradation. Enhancing melatonin signaling, an emerging myocardial protective factor that reduces oxidative stress/apoptosis, is a novel mechanism through which mitochondrial Akt1 could protect against DCM. Under the HFF diet, cardiac mitochondrial Akt1 signaling also caused whole body changes; CAMCAKT mice had 15% less body fat, 30% lower total cholesterol and 42% lower LDL (p&lt;0.05), and showed higher energy expenditure during night cycles and an elevated RER, an indicator for increased carbohydrate metabolism. The diet-induced fatty liver in the CAMCAKT mice was significantly lowered, suggesting that cardiac mitochondrial Akt signaling could remotely modulate hepatic fat metabolism. Liver RNAseq revealed that cholesterol synthesis in the liver was modulated by cardiac mitochondria.
In summary, activating cardiac mitochondrial Akt1 protected against DCM by inhibiting melatonin degradation, and attenuated the development of fatty liver by regulating cholesterol synthesis.

Disclosure
A. Ta: None. Y. Chen: None. Y. Chen: None. H.Y.H. Lin: None. P.H. Wang: Board Member; Self; Dianavi.

Funding
National Institutes of Health (R01HL096987)
1834-P: Neuronal Nitric Oxide Synthase Activity and Hepatic Insulin Resistance
Authors: WANG CHEN , LI QIAN , ZHU YUNXIA 
Published: June 2020

Objective: Neuronal nitric oxide synthase (nNOS) contains PZD domain through which NOS1AP was connected. We reported previously that NOS1AP regulated hepatic insulin sensitivity depending on its PZD binding domain suggesting an involvement of nNOS in NOS1AP effect. Thus, in the present study, we aimed to explore the role of nNOS on hepatic glucose and lipid metabolism, and the mechanism underlined.
Methods: Liver specific nNOS overexpression was achieved by tail-vein-injection of adenovirus-nNOS in C57BL/6 mice fed with a high-fat diet (HFD). nNOS specific inhibitor (L-NPA) was used to change the activity of nNOS. Western blot was used to evaluate the protein expression. Real-time PCR was used to detect the gene expression.
Results: nNOS expressed in livers from humans and mice, and its phosphorylation in Ser1417 increased in the livers of ob/ob and HFD-induced obese mice. Overexpression of nNOS in the livers of HFD-induced obese mice further impaired the glucose tolerance, increased the intrahepatic lipid accumulation, decreased the glycogen storage, and blunted insulin-induced phosphorylation of IRβ and AKT in livers (all P &lt;0.05). Similarly, overexpression of nNOS increased the triglyceride production, decreased the glucose utilization, and insulin-induced phosphorylation of IRβ, AKT and GSK3β in HepG2 cells (all P &lt;0.05). In contrast, inhibition of nNOS with L-NPA in ob/ob mice improved the glucose tolerance and increased insulin-induced phosphorylation of IRβ and AKT in livers (all P &lt;0.05). Moreover, overexpression of nNOS in HepG2 cells increased phosphorylation of P38 MAPK, whereas, inhibition of P38 MAPK with SB203580 significantly reversed the defect in insulin signaling activation -induced by nNOS overexpression.
Conclusions: Hepatic nNOS inhibited insulin signaling pathway through the activation of P38 MAPK, suggesting a role of nNOS as a potential therapeutic target for the prevention and treatment of type 2 diabetes.

Disclosure
C. Wang: None. Q. Li: None. Y. Zhu: None.

Funding
National Natural Science Foundation of China (81670707)
1837-P: Female Hormone Estradiol Regulates Hepatic FGF21 Expression via Wnt Pathway Activation
Authors: SHAO WEIJUAN , BADAKHSHI YASAMAN , JIN TIANRU 
Published: June 2020

β-cat/TCF, formed by β-cat and a TCF family member, serves as the effector of the developmental canonical Wnt signaling cascade. β-cat/TCFs can also function as effectors of metabolic hormones or growth factors during adulthood.
We have demonstrated recently that liver-specific expression of dominant-negative TCF7L2 (TCF7L2DN) led to impaired glucose disposal in both male and female mice. Increased hepatic lipogenesis, however, was observed in male but not in female mice. Our further investigations on such LTCFDN transgenic mouse model revealed the role of estradiol (E2) in stimulating β-cat/TCF activity. E2 reconstitution in WT mice with ovariectomy (OVX) restored the resistance of female mice to HFD induced body weight gain, insulin intolerance and elevation of hepatic lipogenic gene expression. Such beneficial effects of E2 reconstitution, however, were absent in LTCFDN female mice.
To identify downstream metabolic effector/s of Wnt signaling in regulating hepatic lipogenesis, we assessed metabolic hormone expression in LTCFDN and WT littermates. Curiously, hepatic but not adipose tissue FGF-21 level was reduced in male LTCFDN mice. We then directly assessed the effect of E2 on hepatic FGF-21 expression. In WT mice on LFD diet, OVX leads to reduced hepatic FGF-21 mRNA and protein levels, associated with reduced circulating FGF-21 hormone level. These reduction was associated with reduced hepatic β-cat S675 phosphorylation, TCF7 and TCF7L2 expression. In WT mice on HFD, OVX also reduced hepatic FGF-21 mRNA and circulating FGF-21 hormone levels. Such reduction was also restored with E2 reconstitution. Our study hence identified that FGF-21 is likely among the downstream effectors of E2-Wnt signaling cascade in hepatic lipid homeostasis.

Disclosure
W. Shao: None. Y. Badakhshi: None. T. Jin: None.

Funding
Canadian Institutes of Health Research (PJT159735)
1839-P: Glycemic Control Impacts Severity of Hepatic Fibrosis in NAFLD/NASH
Authors: ALEXOPOULOS ANASTASIA-STEFANIA , CROWLEY MATTHEW , WANG YING , GUY CYNTHIA D. , HENAO RICARDO , SEYMOUR KERI A. , SUDAN RANJAN , PORTENIER DANA , DIEHL ANNA MAE , ABDELMALEK MANAL F. , COVIELLO ANDREA D. 
Published: June 2020

T2DM increases risk for advanced fibrosis in NAFLD, however little is known about the impact of glycemic control on fibrosis severity.
Objective: To assess whether glycemic control is associated with severity of fibrosis in NAFLD.
Methods: We utilized the Duke NAFLD Clinical Database to examine the association between HbA1c and fibrosis in patients with biopsy (Bx)-proven NAFLD (n=941). A generalized linear regression model was used (adjusted for age, gender, race, BMI, HLD, eGFR) to assess the association of mean HbA1c (1 year pre- to 90d post-Bx) and fibrosis severity (stage 3-4=advanced vs. 0-2=mild). Patients with ≥3 HbA1c values (n=335) were examined by group-based trajectory analysis using HbA1c over 5 yrs pre- to 90d post-Bx.
Results: Every 1% increase in mean HbA1c was associated with 20% higher odds of advanced fibrosis (OR 1.20, 95%CI 1.02, 1.39 p=0.02). Group-based trajectory analysis identified three glycemic patterns - good, moderate and poor (groups 1,2,3, respectively); proportion of advanced fibrosis increased with worse glycemic control. Group 2 had higher odds of advanced fibrosis than group 1 (OR 4.46, 95%CI 2.29,8.70, p&lt;0.01). Group 3 estimates were limited by small sample size (OR vs. group 1: 2.55, 95% CI 0.87,7.44, p&lt;0.01).
Conclusion: Glycemic control preceding Bx impacts severity of liver fibrosis. We are currently analyzing 65 patients with paired Bx to assess impact of HbA1c trends on change in fibrosis severity.

Disclosure
A. Alexopoulos: None. M. Crowley: None. Y. Wang: None. C.D. Guy: Consultant; Self; CymaBay, HistoIndex, Madrigal, NGM. R. Henao: None. K.A. Seymour: Other Relationship; Self; Gore, Medtronic. R. Sudan: None. D. Portenier: Consultant; Self; Medtronic. Speaker’s Bureau; Self; Novo Nordisk Inc. A. Diehl: None. M.F. Abdelmalek: None. A.D. Coviello: Consultant; Self; GI Dynamics Inc., Novo Nordisk Inc. Research Support; Self; Allergan plc., GENFIT, Orthus Health. Speaker’s Bureau; Self; Novo Nordisk Inc.

Funding
Endocrine Fellows Foundation
184-LB: Incidence of Herpes Zoster in Patients with Type 2 Diabetes and Consequences for Treatment
Authors: POIRRIER JEAN-ETIENNE , NAGAR SAURABH , MEYERS JULIANA , GLASSER LISA , JABBOUR SERGE 
Published: June 2020

Herpes zoster (HZ), or shingles, is a common neurocutaneous disease caused by reactivation of latent varicella-zoster-virus that often includes vesicular rash and neuropathic pain, the latter which may last for months or years. Several studies suggest that type-2 diabetes mellitus (T2DM) may represent an important risk factor for the development of HZ. This retrospective claims database analysis assessed the incidence of HZ in patients with T2DM in the U.S. and measured the impact of HZ on T2DM treatment.
Marketscan family of databases from 2013-2018 (Commercial, Medicare) or 2013-2017 (Medicaid) for adults aged 18 years and older was utilized. Crude rate incidence and incidence rate ratio (IRR) adjusted for age, gender, and payer type were calculated. Diabetes Complications Severity Index (DCSI), Charlson Comorbidity Index (CCI) scores and observed treatment usage (e.g., number of prescriptions, number of covered days) were determined before and after an HZ episode.
The overall crude rate incidence of HZ in patients with T2DM was 1.01% or 0.010 per person per year; in comparison, the overall crude rate incidence of HZ among patients without T2DM was 0.5%. The adjusted IRR was 1.68 (95% confidence interval: 1.67-1.70). Patients with T2DM and HZ had a mean age of 62 years, and 86% were commercially insured. An episode of HZ did not change either the DCSI or the CCI score. Regardless of HZ status, the most common T2DM complications were hypertension (78.9% in patients with T2DM only, 81.2% with T2DM and HZ), chronic pulmonary disease (20.1% and 24.3% respectively) and depression (14.1% and 16.3% respectively). Finally, an episode of HZ did not impact T2DM treatment usage.
In conclusion, patients with T2DM had 1.68 times the risk of having an HZ episode compared to patients without T2DM. An episode of HZ among patients with T2DM does not appear to specifically impact T2DM complications/severity or its treatment.
Acknowledgements: Business and Decision Life Sciences platform for publication coordination.

Disclosure
J. Poirrier: None. S. Nagar: Consultant; Self; GlaxoSmithKline plc. J. Meyers: Research Support; Self; GlaxoSmithKline plc. L. Glasser: Employee; Self; GlaxoSmithKline plc. S. Jabbour: None.

Funding
GlaxoSmithKline Biologicals SA (HO-19-19748)
1840-P: GPR40 Deficiency Is Associated with Steatosis, Hepatic Inflammation, and CD36 Upregulation in C57BL/6 Mice
Authors: LU ZHONGYANG , LI YANCHUN , LOPES-VIRELLA MARIA F. , HUANG YAN 
Published: June 2020

GPR40 is a G-protein coupled receptor for medium and long-chain fatty acids. Since GPR40 is highly expressed in pancreatic islets and GPR40 activation increases glucose-stimulated insulin secretion from pancreatic beta cells, GPR40 is considered as a potential target for treatment of type 2 diabetes mellitus (T2DM). However, although nonalcoholic fatty liver disease (NAFLD) is a common complication of T2DM and GPR40 is also expressed in hepatocytes and macrophages, the role of GPR40 in high-fat diet (HFD)-induced NAFLD in animal models remains unknown. In this study, we fed wild type or GPR40 knockout (KO) C57BL/6 mice low-fat diet (LFD) or HFD for 20 weeks and then analyzed the effect of GPR40 KO on HFD-induced NAFLD. Metabolic assays showed that HFD increased bodyweight, glucose, insulin, insulin resistance, cholesterol and alanine aminotransferase (ALT) as expected, but GPR40 KO did not further change these parameters in HFD-fed mice. Interestingly, in LFD-fed mice, GPR40 KO increased bodyweight, insulin, insulin resistance, cholesterol and ALT. Histological analysis and Oil Red O staining showed that HFD induced steatosis while GPR40 KO only slightly reduced HFD-induced steatosis. Surprisingly, GPR40 KO in LFD-fed mice induced steatosis. Furthermore, study showed that while HFD increased immunostaining of F4/80, a biomarker for macrophages, GPR40 KO also increased F4/80 immunostaining in LFD-fed mice. Finally, we found that while HFD increased mRNA expression of CD36, a scavenger receptor that also imports long-chain fatty acids into cells, by 5-fold in liver, GPR40 KO increased it by 9-fold in LFD-fed mice. Taken together, this study showed that GPR40 deficiency was associated with insulin resistance, dyslipidemia, steatosis and hepatic inflammation in LFD-fed mice. This study also showed that GPR40-deficiency led to a robust upregulation of CD36 expression in liver, which is likely involved in GPR40 deficiency-associated steatosis and hepatic inflammation.

Disclosure
Z. Lu: None. Y. Li: None. M.F. Lopes-Virella: None. Y. Huang: None.

Funding
National Institutes of Health (DE027070); U.S. Department of Veterans Affairs (BX000854)
1844-P: Agpat5 Promotes Obesity-Associated Hyperinsulinemia
Authors: CLAIR SAMANTHA L. ST. , BELISLE SABRINA L. , BRUGGEMAN SYDNEY , LEYVA JAIMES FERNANDA B. , BURGESS BOBBI A. , LI ZHONGGANG , PARKS BRIAN 
Published: June 2020

Hyperinsulinemia in association with obesity is a key contributor to type 2 diabetes. Using a mouse genetic reference population, we identified Agpat5, 1-acylglycerol-3-phosphate O-acyltransferase 5, as a gene associated with plasma insulin levels after high fat feeding. Using a genetic interaction analysis, we also uncovered a relationship between Agpat5 and Foxo1, Forkhead Box O1. Agpat5 is an acyltransferase that produces diverse phospholipids by esterifying lysophospholipids. Foxo1 is an insulin responsive transcription factor. To biologically validate the role of Agpat5 in obesity associated hyperinsulinemia, we treated obese high fat fed mice with an antisense oligonucleotide (ASO) that targets Agpat5 to inhibit its gene expression. We show that Agpat5 ASO treated obese mice have significantly lower fed and fasting plasma insulin, as well as improved glucose tolerance and reduced Foxo1 protein. Analysis of insulin secretion and clearance indicates that Agpat5 ASO treated mice clear insulin more efficiently, as assessed by c-peptide to insulin ratio. To understand the tissue-specific roles of Agpat5 in obesity, we generated liver- and adipose- specific knockout mice. We show that hepatic Agpat5 promotes hepatic insulin resistance and hyperinsulinemia through a mechanism involving hepatic Foxo1. Furthermore, we show that adipose Agpat5 promotes hyperinsulinemia and adiposity. Our studies suggest that Agpat5 promotes hyperinsulinemia in obesity through regulation of Foxo1 signaling and insulin clearance.

Disclosure
S.L. St. Clair: None. S.L. Belisle: None. S. Bruggeman: None. F.B. Leyva Jaimes: None. B.A. Burgess: None. Z. Li: None. B. Parks: None.