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Adiponectin involved in portal flow hepatic extraction of 13C-methacetin in obesity and non-alcoholic fatty liver

Published:April 15, 2021DOI:https://doi.org/10.1016/j.ejim.2021.03.036

      Highlights

      • Obesity and steatosis are linked with altered hepatic extraction efficiency from portal flow
      • Liver steatosis is associated with impaired hepatic microsomal function
      • In obese and steatosis, altered hepatic extraction correlates with adiponectin levels
      • In steatosis, microsomal efficiency correlates with adiponectin levels
      • (13C)-methacetin breath test can early reveal a deranged liver function in obesity/steatosis

      Abstract

      Obesity and non-alcoholic fatty liver disease (NAFLD) are high prevalence, inter-related conditions at increased risk for advanced liver diseases and related mortality. Adiponectin and leptin have divergent roles in the pathogenesis of fat accumulation and NAFLD. However, the relationships between body and liver fat accumulation, early modification of liver function and unbalanced adipokine levels are still scarcely explored. We studied by (13C)-methacetin breath test ((13C)-MBT) 67 adults stratified according to body mass index, and to presence/absence of ultrasonographic nonalcoholic fatty liver disease (uNAFLD). uNAFLD was detected in 20%, 73% and 96% of normal weight, overweight and obese subjects, respectively. The delta over baseline after 15 min (DOB15), a marker of hepatic extraction efficiency from portal blood flow, was lower in obese than in normal weight subjects, and in subjects with-, as compared to those without uNAFLD. The cumulative percent dose recovery after 30 min (cPDR30), a marker of liver microsomal function, was lower in uNAFLD patients. DOB15 was positively correlated with adiponectin levels in obese and in uNAFLD patients. uNAFLD patients also showed a positive correlation between cPDR30 values and adiponectin. Our data indicate the existence of early alterations of liver function in obese and in patients with uNAFLD. These dysfunctions are linked to altered leptin/adiponectin balance and can be identified noninvasively by (13C)-MBT.

      Keywords

      Abbreviations:

      NAFLD (non-alcoholic fatty liver disease), NASH (Non-alcoholic steato-hepatitis), uNAFLD (Ultrasonographic Nonalcoholic Fatty Liver), (13C)-MBT ((13C)-methacetin breath test), ARFI (acoustic radiation force impulse), HOMA (Homeostatic Model Assessment for Insulin Resistance), hsCRP (high-sensitivity C-reactive protein), DOB15 (delta over baseline after 15 minutes), cPDR30 (cumulative percent dose recovery after 30 minutes)
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      References

        • Vernon G
        • Baranova A
        • Younossi ZM.
        Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults.
        Aliment Pharmacol Ther. 2011; 34: 274-285
        • Younossi Z
        • Anstee QM
        • Marietti M
        • Hardy T
        • Henry L
        • Eslam M
        • et al.
        Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention.
        Nat Rev Gastroenterol Hepatol. 2018; 15: 11-20
        • Yun Y
        • Kim HN
        • Lee EJ
        • Ryu S
        • Chang Y
        • Shin H
        • et al.
        Fecal and blood microbiota profiles and presence of nonalcoholic fatty liver disease in obese versus lean subjects.
        PLoS One. 2019; 14
        • Vecchie A
        • Dallegri F
        • Carbone F
        • Bonaventura A
        • Liberale L
        • Portincasa P
        • et al.
        Obesity phenotypes and their paradoxical association with cardiovascular diseases.
        European journal of Internal Medicine. 2018; 48: 6-17
        • Day CP
        • James OF
        Steatohepatitis: a tale of two "hits"?.
        Gastroenterology. 1998; 114: 842-845
        • Farrell GC
        • Larter CZ.
        Nonalcoholic fatty liver disease: from steatosis to cirrhosis.
        Hepatology. 2006; 43: S99-S112
        • Park CC
        • Nguyen P
        • Hernandez C
        • Bettencourt R
        • Ramirez K
        • Fortney L
        • et al.
        Magnetic Resonance Elastography vs Transient Elastography in Detection of Fibrosis and Noninvasive Measurement of Steatosis in Patients With Biopsy-Proven Nonalcoholic Fatty Liver Disease.
        Gastroenterology. 2017; 152 (e2): 598-607
        • Boursier J
        • Vergniol J
        • Guillet A
        • Hiriart JB
        • Lannes A
        • Le Bail B
        • et al.
        Diagnostic accuracy and prognostic significance of blood fibrosis tests and liver stiffness measurement by FibroScan in non-alcoholic fatty liver disease.
        J Hepatol. 2016; 65: 570-578
        • Younossi ZM.
        Non-alcoholic fatty liver disease - A global public health perspective.
        J Hepatol. 2019; 70: 531-544
        • Lindenmeyer CC
        • McCullough AJ.
        The Natural History of Nonalcoholic Fatty Liver Disease-An Evolving View.
        Clin Liver Dis. 2018; 22: 11-21
        • Chang ML
        • Yang Z
        • Yang SS.
        Roles of Adipokines in Digestive Diseases: Markers of Inflammation, Metabolic Alteration and Disease Progression.
        Int J Mol Sci. 2020; 21
        • Caselli C.
        Role of adiponectin system in insulin resistance.
        Mol Genet Metab. 2014; 113: 155-160
        • Yanai H
        • Yoshida H.
        Beneficial Effects of Adiponectin on Glucose and Lipid Metabolism and Atherosclerotic Progression: Mechanisms and Perspectives.
        Int J Mol Sci. 2019; : 20
        • Shabalala SC
        • Dludla PV
        • Mabasa L
        • Kappo AP
        • Basson AK
        • Pheiffer C
        • et al.
        The effect of adiponectin in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and the potential role of polyphenols in the modulation of adiponectin signaling.
        Biomed Pharmacother. 2020; 131110785
        • Silva TE
        • Colombo G
        • Schiavon LL.
        Adiponectin: A multitasking player in the field of liver diseases.
        Diabetes Metab. 2014; 40: 95-107
        • Polyzos SA
        • Toulis KA
        • Goulis DG
        • Zavos C
        • Kountouras J.
        Serum total adiponectin in nonalcoholic fatty liver disease: a systematic review and meta-analysis.
        Metabolism. 2011; 60: 313-326
        • Park KG
        • Park KS
        • Kim MJ
        • Kim HS
        • Suh YS
        • Ahn JD
        • et al.
        Relationship between serum adiponectin and leptin concentrations and body fat distribution.
        Diabetes Res Clin Pract. 2004; 63: 135-142
        • Chessler SD
        • Fujimoto WY
        • Shofer JB
        • Boyko EJ
        • Weigle DS.
        Increased plasma leptin levels are associated with fat accumulation in Japanese Americans.
        Diabetes. 1998; 47: 239-243
        • Ahima RS
        • Flier JS.
        Adipose tissue as an endocrine organ.
        Trends Endocrinol Metab. 2000; 11: 327-332
        • Polyzos SA
        • Aronis KN
        • Kountouras J
        • Raptis DD
        • Vasiloglou MF
        • Mantzoros CS.
        Circulating leptin in non-alcoholic fatty liver disease: a systematic review and meta-analysis.
        Diabetologia. 2016; 59: 30-43
        • Balmer ML
        • Joneli J
        • Schoepfer A
        • Stickel F
        • Thormann W
        • Dufour JF.
        Significance of serum adiponectin levels in patients with chronic liver disease.
        Clin Sci (Lond). 2010; 119: 431-436
        • Kim YS
        • Lee SH
        • Park SG
        • Won BY
        • Chun H
        • Cho DY
        • et al.
        Low levels of total and high-molecular-weight adiponectin may predict non-alcoholic fatty liver in Korean adults.
        Metabolism. 2020; 103154026
        • Schwenzer NF
        • Springer F
        • Schraml C
        • Stefan N
        • Machann J
        • Schick F.
        Non-invasive assessment and quantification of liver steatosis by ultrasound, computed tomography and magnetic resonance.
        J Hepatol. 2009; 51: 433-445
        • Merkel C
        • Bolognesi M
        • Bellon S
        • Bianco S
        • Honisch B
        • Lampe H
        • et al.
        Aminopyrine breath test in the prognostic evaluation of patients with cirrhosis.
        Gut. 1992; 33: 836-842
        • Molina-Molina E
        • Shanmugam H
        • Di Ciaula A
        • Grattagliano I
        • Di Palo DM
        • Palmieri V
        • et al.
        13C-methacetin breath test provides evidence of subclinical liver dysfunction linked to fat storage but not lifestyle.
        Journal of Hepatology Reports. 2020; (in press)
        • Gorowska-Kowolik K
        • Chobot A
        • Kwiecien J.
        (13)C Methacetin Breath Test for Assessment of Microsomal Liver Function: Methodology and Clinical Application.
        Gastroenterology Research and Practice. 2017; 20177397840
        • Lalazar G
        • Pappo O
        • Hershcovici T
        • Hadjaj T
        • Shubi M
        • Ohana H
        • et al.
        A continuous 13C methacetin breath test for noninvasive assessment of intrahepatic inflammation and fibrosis in patients with chronic HCV infection and normal ALT.
        J Viral Hepat. 2008; 15: 716-728
        • Stravitz RT
        • Reuben A
        • Mizrahi M
        • Lalazar G
        • Brown K
        • Gordon SC
        • et al.
        Use of the methacetin breath test to classify the risk of cirrhotic complications and mortality in patients evaluated/listed for liver transplantation.
        J Hepatol. 2015; 63: 1345-1351
        • Portincasa P
        • Grattagliano I
        • Lauterburg BH
        • Palmieri VO
        • Palasciano G
        • Stellaard F.
        Liver breath tests non-invasively predict higher stages of non-alcoholic steatohepatitis.
        Clin Sci (Lond). 2006; 111: 135-143
        • Fierbinteanu-Braticevici C
        • Plesca DA
        • Tribus L
        • Panaitescu E
        • Braticevici B.
        The role of (1)(3)C-methacetin breath test for the non-invasive evaluation of nonalcoholic fatty liver disease.
        Journal of Gastrointestinal and Liver Diseases : JGLD. 2013; 22: 149-156
        • Fierbinteanu-Braticevici C
        • Plesca DA
        • Tribus L
        • Panaitescu E
        • Braticevici B.
        The role of 13C-methacetin breath test for the non-invasive evaluation of nonalcoholic fatty liver disease.
        J Gastrointestin Liver Dis. 2013; 22: 149-156
        • Kempinski R
        • Neubauer K
        • Wieczorek S
        • Dudkowiak R
        • Jasinska M
        • Poniewierka E.
        13C-Methacetin Breath Testing in Patients with Non-Alcoholic Fatty Liver Disease.
        Adv Clin Exp Med. 2016; 25: 77-81
        • Molina-Molina E
        • Shanmugam H
        • Di Ciaula A
        • Grattagliano I
        • Di Palo DM
        • VO Palmieri
        • et al.
        ((13)C)-Methacetin breath test provides evidence of subclinical liver dysfunction linked to fat storage but not lifestyle.
        JHEP Rep. 2021; 3100203
        • Pasarin M
        • Abraldes JG
        • Liguori E
        • Kok B
        • La Mura V
        Intrahepatic vascular changes in non-alcoholic fatty liver disease: Potential role of insulin-resistance and endothelial dysfunction.
        World J Gastroenterol. 2017; 23: 6777-6787
        • Francque S
        • Laleman W
        • Verbeke L
        • Van Steenkiste C
        • Casteleyn C
        • Kwanten W
        • et al.
        Increased intrahepatic resistance in severe steatosis: endothelial dysfunction, vasoconstrictor overproduction and altered microvascular architecture.
        Lab Invest. 2012; 92: 1428-1439
        • van der Graaff D
        • Kwanten WJ
        • Francque SM.
        The potential role of vascular alterations and subsequent impaired liver blood flow and hepatic hypoxia in the pathophysiology of non-alcoholic steatohepatitis.
        Med Hypotheses. 2019; 122: 188-197
        • Francque S
        • Verrijken A
        • Mertens I
        • Hubens G
        • Van Marck E
        • Pelckmans P
        • et al.
        Noncirrhotic human nonalcoholic fatty liver disease induces portal hypertension in relation to the histological degree of steatosis.
        Eur J Gastroenterol Hepatol. 2010; 22: 1449-1457
        • Merrell MD
        • Cherrington NJ.
        Drug metabolism alterations in nonalcoholic fatty liver disease.
        Drug Metab Rev. 2011; 43: 317-334
        • Fisher CD
        • Lickteig AJ
        • Augustine LM
        • Ranger-Moore J
        • Jackson JP
        • Ferguson SS
        • et al.
        Hepatic cytochrome P450 enzyme alterations in humans with progressive stages of nonalcoholic fatty liver disease.
        Drug Metab Dispos. 2009; 37: 2087-2094
        • Uno S
        • Nebert DW
        • Makishima M.
        Cytochrome P450 1A1 (CYP1A1) protects against nonalcoholic fatty liver disease caused by Western diet containing benzo[a]pyrene in mice.
        Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association. 2018; 113: 73-82
        • Schneider A
        • Caspary WF
        • Saich R
        • Dietrich CF
        • Sarrazin C
        • Kuker W
        • et al.
        13C-methacetin breath test shortened: 2-point-measurements after 15 minutes reliably indicate the presence of liver cirrhosis.
        J Clin Gastroenterol. 2007; 41: 33-37
        • Dinesen L
        • Caspary WF
        • Chapman RW
        • Dietrich CF
        • Sarrazin C
        • Braden B.
        13C-methacetin-breath test compared to also noninvasive biochemical blood tests in predicting hepatic fibrosis and cirrhosis in chronic hepatitis C.
        Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2008; 40: 743-748
        • Braden B
        • Faust D
        • Sarrazin U
        • Zeuzem S
        • Dietrich CF
        • Caspary WF
        • et al.
        13C-methacetin breath test as liver function test in patients with chronic hepatitis C virus infection.
        Aliment Pharmacol Ther. 2005; 21: 179-185
        • Holtmeier J
        • Leuschner M
        • Schneider A
        • Leuschner U
        • Caspary WF
        • Braden B.
        13C-methacetin and 13C-galactose breath tests can assess restricted liver function even in early stages of primary biliary cirrhosis.
        Scand J Gastroenterol. 2006; 41: 1336-1341
        • Ilan Y.
        Review article: the assessment of liver function using breath tests.
        Aliment Pharmacol Ther. 2007; 26: 1293-1302
        • Kasicka-Jonderko A
        • Loska D
        • Jonderko K
        • Kaminska M
        • Blonska-Fajfrowska B.
        Interference of acute cigarette smoking with [(1)(3)C]methacetin breath test.
        Isot Environ Health Stud. 2011; 47: 34-41
        • Bonfrate L
        • Grattagliano I
        • Palasciano G
        • Portincasa P.
        Dynamic carbon 13 breath tests for the study of liver function and gastric emptying.
        Gastroenterol Rep (Oxf). 2015; 3: 12-21
        • Grattagliano I
        • Bonfrate L
        • Lorusso M
        • Castorani L
        • de Bari O
        • Portincasa P.
        Exploring liver mitochondrial function by (1)(3)C-stable isotope breath tests: implications in clinical biochemistry.
        Methods Mol Biol. 2015; 1241: 137-152
        • Grattagliano I
        • Bonfrate L
        • Oliveira PJ
        • Castorani L
        • Ruggiero V
        • Valenzano AT
        • et al.
        Breath tests with novel 13C-substrates for clinical studies of liver mitochondrial function in health and disease.
        Eur Rev Med Pharmacol Sci. 2013; 17: 72-81
        • Hydzik P
        • Bielanski W
        • Ponka M
        • Wojcicki M
        • Lubikowski J
        • Pach J
        • et al.
        Usefulness of 13C-methacetin breath test in liver function testing in Amanita phalloides poisoning; breast feeding woman case.
        Clin Toxicol. 2008; 46: 1077-1082
        • Ballestri S
        • Lonardo A
        • Romagnoli D
        • Carulli L
        • Losi L
        • Day CP
        • et al.
        Ultrasonographic fatty liver indicator, a novel score which rules out NASH and is correlated with metabolic parameters in NAFLD.
        Liver Int. 2012; 32: 1242-1252
        • Palmentieri B
        • de Sio I
        • La Mura V
        • Masarone M
        • Vecchione R
        • Bruno S
        • et al.
        The role of bright liver echo pattern on ultrasound B-mode examination in the diagnosis of liver steatosis.
        Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2006; 38: 485-489
        • Liu H
        • Fu J
        • Hong R
        • Liu L
        • Li F.
        Acoustic Radiation Force Impulse Elastography for the Non-Invasive Evaluation of Hepatic Fibrosis in Non-Alcoholic Fatty Liver Disease Patients: A Systematic Review & Meta-Analysis.
        PLoS One. 2015; 10e0127782
        • Hegazy MA
        • Samy MA
        • Tawfik A
        • Naguib MM
        • Ezzat A
        • Behiry ME.
        Abdominal subcutaneous fat thickness and homeostasis model assessment of insulin resistance as simple predictors of nonalcoholic steatohepatitis.
        Diabetes Metab Syndr Obes. 2019; 12: 1105-1111
        • Younossi ZM
        • Koenig AB
        • Abdelatif D
        • Fazel Y
        • Henry L
        • Wymer M.
        Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes.
        Hepatology. 2016; 64: 73-84
        • Argo CK
        • Henry ZH
        Editorial: "Lean" NAFLD: Metabolic Obesity with Normal BMI... Is It in the Genes?.
        Am J Gastroenterol. 2017; 112: 111-113
        • Wang AY
        • Dhaliwal J
        • Mouzaki M.
        Lean non-alcoholic fatty liver disease.
        Clin Nutr. 2019; 38: 975-981
        • Ye Q
        • Zou B
        • Yeo YH
        • Li J
        • Huang DQ
        • Wu Y
        • et al.
        Global prevalence, incidence, and outcomes of non-obese or lean non-alcoholic fatty liver disease: a systematic review and meta-analysis.
        Lancet Gastroenterol Hepatol. 2020; 5: 739-752
        • Chrysavgis L
        • Ztriva E
        • Protopapas A
        • Tziomalos K
        • Cholongitas E.
        Nonalcoholic fatty liver disease in lean subjects: Prognosis, outcomes and management.
        World J Gastroenterol. 2020; 26: 6514-6528
        • Di Palo DM
        • Garruti G
        • Di Ciaula A
        • Molina-Molina E
        • Shanmugam H
        • De Angelis M
        • et al.
        Increased Colonic Permeability and Lifestyles as Contributing Factors to Obesity and Liver Steatosis.
        Nutrients. 2020; 12: E564
        • Molina-Molina E
        • Krawczyk M
        • Stachowska E
        • Lammert F
        • Portincasa P.
        Non-Alcoholic Fatty Liver Disease in Non-Obese Individuals: Prevalence, Pathogenesis and Treatment.
        Clinics and research in hepatology and gastroenterology. 2019; 43: 638-645
        • Doumatey AP
        • Bentley AR
        • Zhou J
        • Huang H
        • Adeyemo A
        • Rotimi CN.
        Paradoxical Hyperadiponectinemia is Associated With the Metabolically Healthy Obese (MHO) Phenotype in African Americans.
        J Endocrinol Metab. 2012; 2: 51-65
        • Lindberg S
        • Jensen JS
        • Bjerre M
        • Frystyk J
        • Flyvbjerg A
        • Jeppesen J
        • et al.
        Low adiponectin levels at baseline and decreasing adiponectin levels over 10 years of follow-up predict risk of the metabolic syndrome.
        Diabetes Metab. 2017; 43: 134-139
        • Yamauchi T
        • Kamon J
        • Ito Y
        • Tsuchida A
        • Yokomizo T
        • Kita S
        • et al.
        Cloning of adiponectin receptors that mediate antidiabetic metabolic effects.
        Nature. 2003; 423: 762-769
        • Ouchi N
        • Kihara S
        • Arita Y
        • Maeda K
        • Kuriyama H
        • Okamoto Y
        • et al.
        Novel modulator for endothelial adhesion molecules: adipocyte-derived plasma protein adiponectin.
        Circulation. 1999; 100: 2473-2476
        • Wolf AM
        • Wolf D
        • Rumpold H
        • Enrich B
        • Tilg H.
        Adiponectin induces the anti-inflammatory cytokines IL-10 and IL-1RA in human leukocytes.
        Biochem Biophys Res Commun. 2004; 323: 630-635
        • Yamamoto K
        • Kiyohara T
        • Murayama Y
        • Kihara S
        • Okamoto Y
        • Funahashi T
        • et al.
        Production of adiponectin, an anti-inflammatory protein, in mesenteric adipose tissue in Crohn's disease.
        Gut. 2005; 54: 789-796
        • Esmaili S
        • Hemmati M
        • Karamian M.
        Physiological role of adiponectin in different tissues: a review.
        Arch Physiol Biochem. 2020; 126: 67-73
        • Lee J
        • Yoon K
        • Ryu S
        • Chang Y
        • Kim HR.
        High-normal levels of hs-CRP predict the development of non-alcoholic fatty liver in healthy men.
        PLoS One. 2017; 12e0172666
        • Kucukoglu O
        • Sowa JP
        • Mazzolini GD
        • Syn WK
        • Canbay A.
        Hepatokines and adipokines in NASH-related hepatocellular carcinoma.
        J Hepatol. 2020;
        • Moschen AR
        • Wieser V
        • Tilg H.
        Adiponectin: key player in the adipose tissue-liver crosstalk.
        Curr Med Chem. 2012; 19: 5467-5473
        • Ghantous CM
        • Farhat R
        • Djouhri L
        • Alashmar S
        • Anlar G
        • Korashy HM
        • et al.
        Molecular Mechanisms of Adiponectin-Induced Attenuation of Mechanical Stretch-Mediated Vascular Remodeling.
        Oxidative medicine and cellular longevity. 2020; 20206425782
        • Kaser S
        • Moschen A
        • Cayon A
        • Kaser A
        • Crespo J
        • Pons-Romero F
        • et al.
        Adiponectin and its receptors in non-alcoholic steatohepatitis.
        Gut. 2005; 54: 117-121
        • Tietge UJ
        • Boker KH
        • Manns MP
        • Bahr MJ.
        Elevated circulating adiponectin levels in liver cirrhosis are associated with reduced liver function and altered hepatic hemodynamics.
        Am J Physiol Endocrinol Metab. 2004; 287: E82-E89
        • Xu H
        • Zhao Q
        • Song N
        • Yan Z
        • Lin R
        • Wu S
        • et al.
        AdipoR1/AdipoR2 dual agonist recovers nonalcoholic steatohepatitis and related fibrosis via endoplasmic reticulum-mitochondria axis.
        Nat Commun. 2020; 11: 5807
        • Shehzad A
        • Iqbal W
        • Shehzad O
        • Lee YS.
        Adiponectin: regulation of its production and its role in human diseases.
        Hormones (Athens). 2012; 11: 8-20
        • Yamauchi T
        • Nio Y
        • Maki T
        • Kobayashi M
        • Takazawa T
        • Iwabu M
        • et al.
        Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions.
        Nat Med. 2007; 13: 332-339
        • Pawlak M
        • Lefebvre P
        • Staels B.
        Molecular mechanism of PPARalpha action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease.
        J Hepatol. 2015; 62: 720-733
        • Baikpour M
        • Ozturk A
        • Dhyani M
        • Mercaldo ND
        • Pierce TT
        • Grajo JR
        • et al.
        Portal Venous Pulsatility Index: A Novel Biomarker for Diagnosis of High-Risk Nonalcoholic Fatty Liver Disease.
        AJR Am J Roentgenol. 2020; 214: 786-791
        • Seifalian AM
        • Chidambaram V
        • Rolles K
        • Davidson BR.
        In vivo demonstration of impaired microcirculation in steatotic human liver grafts.
        Liver Transpl Surg. 1998; 4: 71-77
        • Moran S
        • Mina A
        • Duque X
        • Ortiz-Olvera N
        • Rodriguez-Leal G
        • Alfredo Sierra-Ramirez J
        • et al.
        The utility of the (13)C-methacetin breath test in predicting the long-term survival of patients with decompensated cirrhosis.
        J Breath Res. 2017; 11036011
        • Lefere S
        • Devisscher L
        • Geerts A.
        Angiogenesis in the progression of non-alcoholic fatty liver disease.
        Acta Gastroenterol Belg. 2020; 83: 301-307
        • Kwasniewska M
        • Kozinska J
        • Dziankowska-Zaborszczyk E
        • Kostka T
        • Jegier A
        • Rebowska E
        • et al.
        The impact of long-term changes in metabolic status on cardiovascular biomarkers and microvascular endothelial function in middle-aged men: a 25-year prospective study.
        Diabetol Metab Syndr. 2015; 7: 81
        • Lee S
        • Zhang H
        • Chen J
        • Dellsperger KC
        • Hill MA
        • Zhang C.
        Adiponectin abates diabetes-induced endothelial dysfunction by suppressing oxidative stress, adhesion molecules, and inflammation in type 2 diabetic mice.
        American journal of physiology Heart and circulatory physiology. 2012; 303: H106-H115
        • Wang Z
        • Wu Y
        • Zhang S
        • Zhao Y
        • Yin X
        • Wang W
        • et al.
        The role of NO-cGMP pathway inhibition in vascular endothelial-dependent smooth muscle relaxation disorder of AT1-AA positive rats: protective effects of adiponectin.
        Nitric Oxide. 2019; 87: 10-22
        • Ding W
        • Zhang Q
        • Dong Y
        • Ding N
        • Huang H
        • Zhu X
        • et al.
        Adiponectin protects the rats liver against chronic intermittent hypoxia induced injury through AMP-activated protein kinase pathway.
        Sci Rep. 2016; 6: 34151
        • Afolabi P
        • Wright M
        • Wootton SA
        • Jackson AA.
        Clinical utility of 13C-liver-function breath tests for assessment of hepatic function.
        Dig Dis Sci. 2013; 58: 33-41

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