INTRODUCTION

Excess accumulation of fat in the liver is known as fatty liver disease. Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases in the Western hemisphere, affecting 20% to 30% of the adult population [1]. Approximately 10% to 25% patients with NAFLD can progress to non-alcoholic steatohepatitis (NASH) and 10% to 15% patients with NASH develop hepatocellular carcinoma [2,3]. In addition, NAFLD is closely associated with metabolic syndrome, type 2 diabetes mellitus (T2DM) and cardiovascular morbidity and mortality. Despite these associated pathologies, there is still no specific treatment for NAFLD.

Glucagon-like peptide-1 (GLP-1) is an incretin secreted by L-cells in the small intestine in response to food intake [4]. The main roles of GLP-1 are stimulation of glucose-dependent insulin secretion, inhibition of postprandial glucagon release, delay of gastric emptying, and induction of pancreatic β-cell proliferation [5].

Once in circulation, GLP-1 has a short half-life (1 to 2 minutes) due to rapid degradation by the ubiquitous endogenous enzyme dipeptidyl peptidase-4 (DPP-4). To overcome this obstacle, GLP-1 receptor agonists that have increased resistance to DPP-4 (such as exenatide and liraglutide) or DPP-4 inhibitors (such as sitagliptin, vildagliptin, saxagliptin, alogliptin, and linagliptin) have been used in animal and human studies [6,7].

Recent studies have shown that exendin-4 could improve hepatic steatosis by modulation of lipid metabolism and hepatic insulin signaling in ob/ob mice and in human hepatocyte [8,9]. Additional studies have demonstrated that treatment with exendin-4 and liraglutide could reduce steatosis by enhancing autophagy. Treatment with exendin-4 and liraglutide leads to reduced endoplasmic reticulum (ER) stress-related apoptosis in human hepatocytes treated with fatty acids as well as in mice fed a high fat diet, respectively [10]. In this review, we present the pleiotropic effects of GLP-1 on reducing NAFLD.

LIPID METABOLISM IN NORMAL AND NAFLD PATIENTS

The liver, as a key organ for lipid homeostasis, has roles in various aspect of energy metabolism. Hepatic lipid homeostasis is usually maintained through balance between the influx or production of fatty acids and their use for oxidation or secretion as very low density lipoprotein (VLDL) triglycerides [11-13]. Disruption of hepatic lipid homeostasis causes liver dysfunction, eventually leading to liver disease.

Hepatic steatosis is associated with the alteration of nuclear receptors, membrane transport proteins and cellular enzymes [14,15]. Sterol regulatory element binding protein1c (SREBP-1c) transcription factor and peroxisome proliferator-activated receptor α (PPARα) are essential regulators for steatosis in obese patients. Enhancement in the SREBP-1c/PPARα ratio, an indication that lipogenesis is higher than fatty acid oxidation, was found in obese patients with hepatic steatosis [16]. Additional studies demonstrated that SREBP-1c -/- mice had impaired induction of hepatic genes coding for fatty acid biosynthesis (e.g., acetyl-CoA carboxylase, fatty acid synthase, and stearoyl-CoA desaturase) compared to wild type mice [17]. These results suggest that NAFLD is caused by both increased lipid storage (from circulating fatty acid uptake and de novo lipogenesis) and decreased lipid removal (via fatty acid oxidation or VLDL-triglycerides secretion).

GLP-1 SIGNALING IN NORMAL AND NAFLD PATIENTS

Pleiotropic effects of GLP-1 on glucose metabolism, appetite, weight, blood pressure, cardiovascular risk factors, cardiovascular function, and the central nervous system have been reported [18]. GLP-1 achieves its roles by binding to its specific receptor (GLP-1R) on human hepatocytes [9]. In addition, we recently reported that exendin-4 increases expression of GLP-1R in a dose-dependent manner in human hepatoma cell lines [19].

Several human and animal studies have demonstrated the therapeutic effects of GLP-1 receptor agonist in slowing the progression of NAFLD. Exenatide therapy decreased hepatic fat accumulation, insulin resistance, and the risk of cardiovascular disease in patient with T2DM [20] and also improved fatty acid β-oxidation and insulin sensitivity in the livers of rats on a high fat diet [21]. Hepatic gluconeogenesis and insulin sensitivity were improved in ob/ob mice treated with recombinant adenovirus expressing GLP-1 (rAd-GLP-1) [22].

Protective effects of GLP-1 against hepatic steatosis were found in only diet-induced obese mice [23]. Sitagliptin, a DPP-4 inhibitor, showed a decrease in liver triglyceride content, expression of lipogenesis genes and gluconeogenesis in wild type mice [24]. Ultimately, exendin-4 may play role as a novel treatment of NAFLD via direct effect on hepatic lipid and glucose metabolism.

GLP-1 EFFECT ON FATTY ACID OXIDATION IN LIVER

In mammalian liver, fatty acids oxidation serves as a source for energy generation and occurs in both the mitochondria and the peroxisomes. Short and medium-chain fatty acids (SCFAs: <6 carbons long and MCFAs: 6 to 12 carbons long) are oxidized in the mitochondria, long-chain fatty acids (LCFAs: C12 to C20) are oxidized in both the mitochondria and peroxisomes, and very long-chain fatty acids (VLCFAs: >C20) are preferentially oxidized in the peroxisomes [25]. However, excess fatty acids can impair fatty acid oxidation by inhibiting the activities of enzymes involved in fatty acid oxidation [26]. PPARα is a transcriptional factor regulating the expression of a number of genes involved in mitochondrial and peroxisomal fatty acid β-oxidation [27,28].

Exendin-4 significantly increases the expression of PPARα and acyl-Coenzyme A oxidase (ACOX) mRNA in ob/ob mice [8]. Hepatocytes isolated from rats with NASH demonstrated reduced expression of hepatic PPARα and its downstream target genes: ACOX and carnitine palmitoyltransferase 1A (CPT1A). ACOX is a rate-limiting enzyme involved in peroxisomal fatty acid β-oxidation and CPT1A is a key enzyme allowing the initial transport of fatty acids into mitochondria for β-oxidation. Expression of PPARα, and subsequently ACOX and CPT1A, was improved by exendin-4 treatment [21].

GLP-1 EFFECT ON AMPK, NAMPT, AND SIRT SIGNALING

AMP-activated protein kinase (AMPK) and silent mating type information regulation 2 homolog (sirtuin, SIRT) 1 are metabolic sensors regulating energy homeostasis and various intracellular systems. These include fatty acid oxidation, lipogenesis, glucose uptake, gluconeogenesis, mitochondria biosynthesis, and insulin sensitivity [29,30]. They are also involved in mediating the effect of adiponectin in inhibiting the accumulation of liver fat [31]. AMPK and SIRT1 are activated by an AMP and NAD⁺ dependent mechanism and acts through regulation of phosphorylation and deacetylation of their targets, respectively. PGC-1α is a common target of the two metabolic sensors, and has been shown to have protective effects in patients with metabolic diseases [29].

Nampt/visfatin is a mammalian NAD+ biosynthetic enzyme that controls SIRT1 activity by mediating the conversion of nicotinamide (NAM) to NAD⁺ [30]. Activated SIRT1 enhances AMPK activity via an LKB1-dependent manner in human hepatocytes (Fig. 1A) [32]. However, the precise mechanism of interaction between AMPK and SIRT1 is still controversial and varies with tissue and condition. Cantó et al. [33] reported that AMPK regulates SIRT1 activity by increasing cellular NAD⁺ levels in mouse skeletal muscle (Fig. 1B).

Recent studies reported that GLP-1 increases the phosphorylation of AMPK in hepatocytes and reverses hepatic steatosis by stimulating fatty acid oxidation [8,31,32]. Moreover, we recently demonstrated that activating GLP-1 receptor by exendin-4 treatment enhances the expression of NAMPT, SIRT1, and AMPK in mouse liver. SIRT1 inhibitor (NAM) leads to a decrease in phosphorylation of AMPK in human hepatocytes, indicating that SIRT1 stimulates AMPK (Fig. 2) [19]. Thus, GLP-1 could improve hepatic lipid metabolism by regulation of NAMPT/SIRT1/AMPK signaling.

GLP-1 EFFECT ON LIVER FUNCTION AND GLUCOSE METABOLISM IN HUMAN

The liver has a vast range functions in the body, including immunity against infection, synthesis of proteins and cholesterol, detoxification, glycogen storage, excretion of bile for fat digestion, and regulation of metabolism. However, insults such as alcohol, autoimmune malfunction, hereditary diseases, and metabolic diseases could result in liver dysfunction.

In a study investigating human hepatocytes treated with fatty acids, exenatide was shown to reduce fatty acid storage and improve hepatocyte viability and markers of autophagy [10]. A clinical trial evaluating the effects of exenatide in patients with T2DM over a period of 3 years revealed that treatment lead to significant improvements in hepatic markers, such as elevated liver enzymes, and other cardiovascular risk factors were significantly improved [34]. A case study exploring the efficacy of exenatide therapy in a 59-year-old NAFLD patient, reported a 73% reduction in hepatic fat content and significant improvements in liver enzymes 44 weeks post-treatment [20].

GLP-1 has recently been shown to increase hepatic insulin signaling and sensitivity [9]. A modified glucose clamp study demonstrated that exenatide reduces postprandial glucose by increasing the hepatic uptake of exogenous glucose [35]. Furthermore, GLP-1 in obese mice reduces hepatic gluconeogenesis by inhibiting phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) [22]. Park et al. [36] reported that exendin-4 treatment decreases hepatic glucose output at hyperinsulinemic states and promotes hepatic insulin signaling by potentiating tyrosine phosphorylation of the insulin receptor substrate-2 in 90% pancreatectomized diabetic rats fed high fat (40% energy from fat) diets.

CONCLUSION

Disruption of lipid metabolic homeostasis has been recognized as a major cause of NAFLD, which is associated with insulin resistance, T2DM, obesity, and cardiovascular disease. Although the incretin GLP-1 has been widely studied for its effects on stimulation of glucose-dependent insulin secretion in pancreatic β-cell, GLP-1 receptor agonists have other important effects in peripheral tissues. Treatment with GLP-1 mimetics improves hepatic insulin signaling in NAFLD animal models, and these effects could be invoked by direct stimulation of hepatic GLP-1 receptor. GLP-1 is expected to have pleiotropic effects on the liver, and more research is needed to explore its mechanism.

Acknowledgements

ACKNOWLEDGMENTS

This work was supported by the Young Investigator Award 2011 from the Korean Diabetes Association and the Korea Science and Engineering Foundation by the Ministry of Education, Science and Technology (S-2010-1115-000) to Won-Young Lee.

NOTES

No potential conflicts of interest relevant to this article were reported.

REFERENCES

• 1. Ruhl CE, Everhart JE. Epidemiology of nonalcoholic fatty liver. Clin Liver Dis 2004;8:501-519. ArticlePubMed
• 2. Vanni E, Bugianesi E, Kotronen A, De Minicis S, Yki-Jarvinen H, Svegliati-Baroni G. From the metabolic syndrome to NAFLD or vice versa? Dig Liver Dis 2010;42:320-330. ArticlePubMed
• 3. Kim CH, Younossi ZM. Nonalcoholic fatty liver disease: a manifestation of the metabolic syndrome. Cleve Clin J Med 2008;75:721-728. ArticlePubMed
• 4. Kim W, Egan JM. The role of incretins in glucose homeostasis and diabetes treatment. Pharmacol Rev 2008;60:470-512. ArticlePubMedPMC
• 5. MacDonald PE, El-Kholy W, Riedel MJ, Salapatek AM, Light PE, Wheeler MB. The multiple actions of GLP-1 on the process of glucose-stimulated insulin secretion. Diabetes 2002;51(Suppl 3):S434-S442. ArticlePubMedPDF
• 6. Ahren B, Schmitz O. GLP-1 receptor agonists and DPP-4 inhibitors in the treatment of type 2 diabetes. Horm Metab Res 2004;36:867-876. ArticlePubMed
• 7. Bourdel-Marchasson I, Schweizer A, Dejager S. Incretin therapies in the management of elderly patients with type 2 diabetes mellitus. Hosp Pract (Minneap) 2011;39:7-21. Article
• 8. Ding X, Saxena NK, Lin S, Gupta NA, Anania FA. Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob/ob mice. Hepatology 2006;43:173-181. ArticlePubMedPMC
• 9. Gupta NA, Mells J, Dunham RM, Grakoui A, Handy J, Saxena NK, Anania FA. Glucagon-like peptide-1 receptor is present on human hepatocytes and has a direct role in decreasing hepatic steatosis in vitro by modulating elements of the insulin signaling pathway. Hepatology 2010;51:1584-1592. ArticlePubMedPMC
• 10. Sharma S, Mells JE, Fu PP, Saxena NK, Anania FA. GLP-1 analogs reduce hepatocyte steatosis and improve survival by enhancing the unfolded protein response and promoting macroautophagy. PLoS One 2011;6:e25269ArticlePubMedPMC
• 11. Adiels M, Taskinen MR, Boren J. Fatty liver, insulin resistance, and dyslipidemia. Curr Diab Rep 2008;8:60-64. ArticlePubMedPDF
• 12. Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest 2005;115:1343-1351. ArticlePubMedPMC
• 13. Liu Q, Bengmark S, Qu S. The role of hepatic fat accumulation in pathogenesis of non-alcoholic fatty liver disease (NAFLD). Lipids Health Dis 2010;9:42ArticlePubMedPMCPDF
• 14. Reddy JK, Rao MS. Lipid metabolism and liver inflammation II Fatty liver disease and fatty acid oxidation. Am J Physiol Gastrointest Liver Physiol 2006;290:G852-G858. ArticlePubMed
• 15. Musso G, Gambino R, Cassader M. Recent insights into hepatic lipid metabolism in non-alcoholic fatty liver disease (NAFLD). Prog Lipid Res 2009;48:1-26. ArticlePubMed
• 16. Pettinelli P, Del Pozo T, Araya J, Rodrigo R, Araya AV, Smok G, Csendes A, Gutierrez L, Rojas J, Korn O, Maluenda F, Diaz JC, Rencoret G, Braghetto I, Castillo J, Poniachik J, Videla LA. Enhancement in liver SREBP-1c/PPAR-alpha ratio and steatosis in obese patients: correlations with insulin resistance and n-3 long-chain polyunsaturated fatty acid depletion. Biochim Biophys Acta 2009;1792:1080-1086. PubMed
• 17. Shimomura I, Bashmakov Y, Horton JD. Increased levels of nuclear SREBP-1c associated with fatty livers in two mouse models of diabetes mellitus. J Biol Chem 1999;274:30028-30032. ArticlePubMed
• 18. Pratley RE. The new science of GLP-1: effects beyond glucose control. Johns Hopkins Adv Stud Med 2008;8:393-399.
• 19. Lee J, Hong SW, Chae SW, Kim DH, Choi JH, Bae JC, Park SE, Rhee EJ, Park CY, Oh KW, Park SW, Kim SW, Lee WY. Exendin-4 improves steatohepatitis by increasing Sirt1 expression in high-fat diet-induced obese C57BL/6J mice. PLoS One 2012;7:e31394ArticlePubMedPMC
• 20. Tushuizen ME, Bunck MC, Pouwels PJ, van Waesberghe JH, Diamant M, Heine RJ. Incretin mimetics as a novel therapeutic option for hepatic steatosis. Liver Int 2006;26:1015-1017. ArticlePubMed
• 21. Svegliati-Baroni G, Saccomanno S, Rychlicki C, Agostinelli L, De Minicis S, Candelaresi C, Faraci G, Pacetti D, Vivarelli M, Nicolini D, Garelli P, Casini A, Manco M, Mingrone G, Risaliti A, Frega GN, Benedetti A, Gastaldelli A. Glucagon-like peptide-1 receptor activation stimulates hepatic lipid oxidation and restores hepatic signalling alteration induced by a high-fat diet in nonalcoholic steatohepatitis. Liver Int 2011;31:1285-1297. ArticlePubMed
• 22. Lee YS, Shin S, Shigihara T, Hahm E, Liu MJ, Han J, Yoon JW, Jun HS. Glucagon-like peptide-1 gene therapy in obese diabetic mice results in long-term cure of diabetes by improving insulin sensitivity and reducing hepatic gluconeogenesis. Diabetes 2007;56:1671-1679. ArticlePubMedPDF
• 23. Tomas E, Wood JA, Stanojevic V, Habener JF. GLP-1-derived nonapeptide GLP-1(28-36)amide inhibits weight gain and attenuates diabetes and hepatic steatosis in diet-induced obese mice. Regul Pept 2011;169:43-48. ArticlePubMed
• 24. Shirakawa J, Fujii H, Ohnuma K, Sato K, Ito Y, Kaji M, Sakamoto E, Koganei M, Sasaki H, Nagashima Y, Amo K, Aoki K, Morimoto C, Takeda E, Terauchi Y. Diet-induced adipose tissue inflammation and liver steatosis are prevented by DPP-4 inhibition in diabetic mice. Diabetes 2011;60:1246-1257. ArticlePubMedPMCPDF
• 25. Bechmann LP, Hannivoort RA, Gerken G, Hotamisligil GS, Trauner M, Canbay A. The interaction of hepatic lipid and glucose metabolism in liver diseases. J Hepatol 2012;56:952-964. ArticlePubMed
• 26. Hettema EH, Tabak HF. Transport of fatty acids and metabolites across the peroxisomal membrane. Biochim Biophys Acta 2000;1486:18-27. ArticlePubMed
• 27. Minnich A, Tian N, Byan L, Bilder G. A potent PPARalpha agonist stimulates mitochondrial fatty acid beta-oxidation in liver and skeletal muscle. Am J Physiol Endocrinol Metab 2001;280:E270-E279. PubMed
• 28. Hashimoto T, Fujita T, Usuda N, Cook W, Qi C, Peters JM, Gonzalez FJ, Yeldandi AV, Rao MS, Reddy JK. Peroxisomal and mitochondrial fatty acid beta-oxidation in mice nullizygous for both peroxisome proliferator-activated receptor alpha and peroxisomal fatty acyl-CoA oxidase. Genotype correlation with fatty liver phenotype. J Biol Chem 1999;274:19228-19236. PubMed
• 29. Canto C, Auwerx J. PGC-1alpha, SIRT1 and AMPK, an energy sensing network that controls energy expenditure. Curr Opin Lipidol 2009;20:98-105. PubMedPMC
• 30. Ruderman NB, Xu XJ, Nelson L, Cacicedo JM, Saha AK, Lan F, Ido Y. AMPK and SIRT1: a long-standing partnership? Am J Physiol Endocrinol Metab 2010;298:E751-E760. ArticlePubMedPMC
• 31. Shen Z, Liang X, Rogers CQ, Rideout D, You M. Involvement of adiponectin-SIRT1-AMPK signaling in the protective action of rosiglitazone against alcoholic fatty liver in mice. Am J Physiol Gastrointest Liver Physiol 2010;298:G364-G374. ArticlePubMed
• 32. Hou X, Xu S, Maitland-Toolan KA, Sato K, Jiang B, Ido Y, Lan F, Walsh K, Wierzbicki M, Verbeuren TJ, Cohen RA, Zang M. SIRT1 regulates hepatocyte lipid metabolism through activating AMP-activated protein kinase. J Biol Chem 2008;283:20015-20026. ArticlePubMedPMC
• 33. Canto C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, Milne JC, Elliott PJ, Puigserver P, Auwerx J. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 2009;458:1056-1060. ArticlePubMedPMCPDF
• 34. Klonoff DC, Buse JB, Nielsen LL, Guan X, Bowlus CL, Holcombe JH, Wintle ME, Maggs DG. Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. Curr Med Res Opin 2008;24:275-286. ArticlePubMed
• 35. Zheng D, Ionut V, Mooradian V, Stefanovski D, Bergman RN. Exenatide sensitizes insulin-mediated whole-body glucose disposal and promotes uptake of exogenous glucose by the liver. Diabetes 2009;58:352-359. ArticlePubMedPMCPDF
• 36. Park S, Hong SM, Ahn IS. Exendin-4 and exercise improve hepatic glucose homeostasis by promoting insulin signaling in diabetic rats. Metabolism 2010;59:123-133. ArticlePubMed

Fig. 1

Proposed regulatory mechanisms between silent mating type information regulation 2 homolog (SIRT1) and AMP-activated protein kinase (AMPK). (A) Activation of SIRT by activator leads to deacetylation of Lys48 residues on LKB1. LKB1 moves to the cytoplasm and then, phosphorylates and activates the AMPK. (B) The enhancement of AMP/ATP ratio stimulates AMPK activity. Activated AMPK regulates SIRT1, an NAD⁺-dependent protein deacetylase, by increasing NAD⁺ levels. NAM, nicotinamide; NAMPT, nicotinamide phosphoribosyltransferase (Adapted from Cantó et al., Curr Opin Lipidol 2009;20:98-105 [29]).

Fig. 2

Regulation of glucagon-like peptide-1 receptor (GLP-1R), SIRT1 and AMPK by exendin-4 (Ex-4) in HepG2 and Huh7 cells. (A) Cells were treated with 50, 100, or 500 nM Ex-4 for 24 hours. GLP-1R and β-actin were measured by western blot and real-time PCR. GLP-1R was normalized to β-actin. (B) Cells given 0.4 mM palmitic acid (PA) were treated with either vehicle or 50 to 100 nM Ex-4 for 24 hours. (C) Cells given 0.4 mM palmitic acid were treated with 100 nM Ex-4 in the absence or presence of 10 mM nicotinamide (NAM) or 10 µM compound C (CC) for 24 hours. (B, C) SIRT1, phosphorylated AMPKα at threonine 172, AMPK, and β-actin were measured by Western blot in HepG2 cells. SIRT1 and phosphorylated AMPKα were normalized to the β-actin and total AMPKα of each sample, respectively. ^aP<0.05, ^bP<0.01 compared with control, ^cP<0.05, compared with PA, and ^dP<0.05 compared with Ex-4 (Adapted from Lee J, et al. PLoS One 2012;7:e31394 [19]).

Figure & Data

References

Citations

Citations to this article as recorded by  

• The intestine as an endocrine organ and the role of gut hormones in metabolic regulation
  Rula Bany Bakar, Frank Reimann, Fiona M. Gribble
  Nature Reviews Gastroenterology & Hepatology.2023; 20(12): 784.     CrossRef
• GLP-1 Receptor Agonists in Non-Alcoholic Fatty Liver Disease: Current Evidence and Future Perspectives
  Riccardo Nevola, Raffaella Epifani, Simona Imbriani, Giovanni Tortorella, Concetta Aprea, Raffaele Galiero, Luca Rinaldi, Raffaele Marfella, Ferdinando Carlo Sasso
  International Journal of Molecular Sciences.2023; 24(2): 1703.     CrossRef
• From Non-Alcoholic Fatty Liver Disease to Liver Cancer: Microbiota and Inflammation as Key Players
  Avilene Rodríguez-Lara, Ascensión Rueda-Robles, María José Sáez-Lara, Julio Plaza-Diaz, Ana I. Álvarez-Mercado
  Pathogens.2023; 12(7): 940.     CrossRef
• Investigating the Opposing Effect of Two Different Green Tea Supplements on Oxidative Stress, Mitochondrial Function and Cell Viability in HepG2 Cells
  Aparna Shil, Chris Davies, Lata Gautam, Justin Roberts, Havovi Chichger
  Journal of Dietary Supplements.2022; 19(4): 459.     CrossRef
• Antiobesity therapeutics with complementary dual‐agonist activities at glucagon and glucagon‐like peptide 1 receptors
  Bong Gyu Park, Gyeong Min Kim, Hye‐Jin Lee, Jae Ha Ryu, Dong‐Hoon Kim, Jae‐Young Seong, Soojeong Kim, Zee‐Yong Park, Young‐Joon Kim, Jaemin Lee, Jae Il Kim
  Diabetes, Obesity and Metabolism.2022; 24(1): 50.     CrossRef
• The anti-inflammatory feature of glucagon-like peptide-1 and its based diabetes drugs—Therapeutic potential exploration in lung injury
  Juan Pang, Jia Nuo Feng, Wenhua Ling, Tianru Jin
  Acta Pharmaceutica Sinica B.2022; 12(11): 4040.     CrossRef
• Deficiency of peroxisomal NUDT7 stimulates de novo lipogenesis in hepatocytes
  Jinsoo Song, In-Jeoung Baek, Sujeong Park, Jinjoo Oh, Deokha Kim, Kyung Song, Mi Kyung Kim, Hye Won Lee, Byoung Kuk Jang, Eun-Jung Jin
  iScience.2022; 25(10): 105135.     CrossRef
• Gut–Liver Axis and Non-Alcoholic Fatty Liver Disease: A Vicious Circle of Dysfunctions Orchestrated by the Gut Microbiome
  Salvatore Pezzino, Maria Sofia, Gloria Faletra, Chiara Mazzone, Giorgia Litrico, Gaetano La Greca, Saverio Latteri
  Biology.2022; 11(11): 1622.     CrossRef
• Efficacy and safety of semaglutide for weight management: evidence from the STEP program
  Anastassia Amaro, Danny Sugimoto, Sean Wharton
  Postgraduate Medicine.2022; 134(sup1): 5.     CrossRef
• Incretin Hormones in Obesity and Related Cardiometabolic Disorders: The Clinical Perspective
  Joanna Michałowska, Ewa Miller-Kasprzak, Paweł Bogdański
  Nutrients.2021; 13(2): 351.     CrossRef
• Insights into the Impact of Microbiota in the Treatment of NAFLD/NASH and Its Potential as a Biomarker for Prognosis and Diagnosis
  Julio Plaza-Díaz, Patricio Solis-Urra, Jerónimo Aragón-Vela, Fernando Rodríguez-Rodríguez, Jorge Olivares-Arancibia, Ana I. Álvarez-Mercado
  Biomedicines.2021; 9(2): 145.     CrossRef
• A comprehensive review for gut microbes: technologies, interventions, metabolites and diseases
  Changlu Qi, Ping Wang, Tongze Fu, Minke Lu, Yiting Cai, Xu Chen, Liang Cheng
  Briefings in Functional Genomics.2021; 20(1): 42.     CrossRef
• Update on the effects of GLP-1 receptor agonists for the treatment of polycystic ovary syndrome
  Maka Siamashvili, Stephen N. Davis
  Expert Review of Clinical Pharmacology.2021; 14(9): 1081.     CrossRef
• Mechanistic and physiological approaches of fecal microbiota transplantation in the management of NAFLD
  Manisha Gupta, Pawan Krishan, Amarjot Kaur, Sandeep Arora, Nirupma Trehanpati, Thakur Gurjeet Singh, Onkar Bedi
  Inflammation Research.2021; 70(7): 765.     CrossRef
• Retrospective analysis (2009–2017) of factors associated with progression and regression of non-alcoholic fatty liver disease (Hepatic steatosis) in patients with type 2 diabetes seen at a tertiary diabetes centre in Southern India
  Nithyanantham Kamalraj, Madhanagopal Sathishkumar, Mani Arunvignesh, Viswanathan Baskar, Saravanan Jebarani, Anandakumar Amutha, Mohan Deepa, Coimbatore Subramanyam Shanthi Rani, Sundaramoorthy Chandru, Ranjit Unnikrishnan, Ranjit Mohan Anjana, Mardavada
  Diabetes & Metabolic Syndrome: Clinical Research & Reviews.2021; 15(5): 102261.     CrossRef
• Gastrointestinal Hormones in Healthy Adults: Reliability of Repeated Assessments and Interrelations with Eating Habits and Physical Activity
  Silke M. Wortha, Katharina A. Wüsten, Veronica A. Witte, Nicole Bössel, Wolfram Keßler, Antje Vogelgesang, Agnes Flöel
  Nutrients.2021; 13(11): 3809.     CrossRef
• Role of ATP-binding cassette transporter A1 in suppressing lipid accumulation by glucagon-like peptide-1 agonist in hepatocytes
  Jingya Lyu, Hitomi Imachi, Kensaku Fukunaga, Seisuke Sato, Toshihiro Kobayashi, Tao Dong, Takanobu Saheki, Mari Matsumoto, Hisakazu Iwama, Huanxiang Zhang, Koji Murao
  Molecular Metabolism.2020; 34: 16.     CrossRef
• Effects of synbiotic consumption on lipid profile: a systematic review and meta-analysis of randomized controlled clinical trials
  Amir Hadi, Ehsan Ghaedi, Saman Khalesi, Makan Pourmasoumi, Arman Arab
  European Journal of Nutrition.2020; 59(7): 2857.     CrossRef
• Glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) for the management of nonalcoholic fatty liver disease (NAFLD): A systematic review
  Xiaodan Lv, Yongqiang Dong, Lingling Hu, Feiyu Lu, Changyu Zhou, Shaoyou Qin
  Endocrinology, Diabetes & Metabolism.2020;[Epub]     CrossRef
• Genetic engineering of novel super long-acting Exendin-4 chimeric protein for effective treatment of metabolic and cognitive complications of obesity
  Jong Youl Lee, Taehoon Park, Eunmi Hong, Reeju Amatya, Kyung-Ah Park, Young-Hoon Park, Kyoung Ah Min, Minki Jin, Sumi Lee, Seungmi Hwang, Gu Seob Roh, Meong Cheol Shin
  Biomaterials.2020; 257: 120250.     CrossRef
• A look to the future in non‐alcoholic fatty liver disease: Are glucagon‐like peptide‐1 analogues or sodium‐glucose co‐transporter‐2 inhibitors the answer?
  Rebecca K. Vincent, David M. Williams, Marc Evans
  Diabetes, Obesity and Metabolism.2020; 22(12): 2227.     CrossRef
• A systematic review and meta-analysis of probiotic consumption and metabolic status of athletes
  Atefeh As’Habi, Maryam Nazari, Hossein Hajianfar, Arman Arab, Zeinab Faghfoori
  International Journal of Food Properties.2020; 23(1): 941.     CrossRef
• The Gut Barrier, Intestinal Microbiota, and Liver Disease: Molecular Mechanisms and Strategies to Manage
  Julio Plaza-Díaz, Patricio Solís-Urra, Fernando Rodríguez-Rodríguez, Jorge Olivares-Arancibia, Miguel Navarro-Oliveros, Francisco Abadía-Molina, Ana I. Álvarez-Mercado
  International Journal of Molecular Sciences.2020; 21(21): 8351.     CrossRef
• Pathophysiology of NAFLD and NASH in Experimental Models: The Role of Food Intake Regulating Peptides
  L. Kořínková, V. Pražienková, L. Černá, A. Karnošová, B. Železná, J. Kuneš, Lenka Maletínská
  Frontiers in Endocrinology.2020;[Epub]     CrossRef
• Have a heart: failure to increase GLP-1 caused by heart failure increases the risk of diabetes
  Michael J. Ryan
  Clinical Science.2020; 134(23): 3119.     CrossRef
• Unraveling the Role of Leptin in Liver Function and Its Relationship with Liver Diseases
  Maite Martínez-Uña, Yaiza López-Mancheño, Carlos Diéguez, Manuel A. Fernández-Rojo, Marta G. Novelle
  International Journal of Molecular Sciences.2020; 21(24): 9368.     CrossRef
• The Role of GLP1 in Rat Steatotic and Non-Steatotic Liver Transplantation from Cardiocirculatory Death Donors
  Cindy G. Avalos-de León, Mónica B. Jiménez-Castro, María Eugenia Cornide-Petronio, Araní Casillas-Ramírez, Carmen Peralta
  Cells.2019; 8(12): 1599.     CrossRef
• LRG ameliorates steatohepatitis by activating the AMPK/mTOR/SREBP1 signaling pathway in C57BL/6J mice fed a high‑fat diet
  Tao Hao, Hongying Chen, Sisi Wu, Haoming Tian
  Molecular Medicine Reports.2019;[Epub]     CrossRef
• Liraglutide alters hepatic metabolism in high-fat fed obese mice: A bioinformatic prediction and functional analysis
  Isabelle Arruda Barbosa, Eloá Mangabeira Santos, Alanna Fernandes Paraíso, Pablo Vinicyus Ferreira Chagas, Luís Paulo Oliveira, João Marcus Oliveira Andrade, Lucyana Conceição Farias, Bruna Mara Aparecida de Carvalho, Alfredo Maurício Batista de Paula, An
  Meta Gene.2019; 20: 100553.     CrossRef
• Dipeptidyl peptidase‐4 inhibitors and aerobic exercise synergistically protect against liver injury in ovariectomized rats
  Nagat Younan, Samah Elattar, Mira Farouk, Laila Rashed, Suzanne Estaphan
  Physiological Reports.2019;[Epub]     CrossRef
• Microbial Metabolites Determine Host Health and the Status of Some Diseases
  Panida Sittipo, Jae-won Shim, Yun Lee
  International Journal of Molecular Sciences.2019; 20(21): 5296.     CrossRef
• Compound K attenuates glucose intolerance and hepatic steatosis through AMPK-dependent pathways in type 2 diabetic OLETF rats
  Yoo-Cheol Hwang, Da-Hee Oh, Moon Chan Choi, Sang Yeoul Lee, Kyu-Jeong Ahn, Ho-Yeon Chung, Sung-Jig Lim, Sung Hyun Chung, In-Kyung Jeong
  The Korean Journal of Internal Medicine.2018; 33(2): 347.     CrossRef
• Liraglutide attenuates partial warm ischemia-reperfusion injury in rat livers
  Ahmed A. Abdelsameea, Noha A.T. Abbas, Samar M. Abdel Raouf
  Naunyn-Schmiedeberg's Archives of Pharmacology.2017; 390(3): 311.     CrossRef
• Natural alkaloid bouchardatine ameliorates metabolic disorders in high‐fat diet‐fed mice by stimulating the sirtuin 1/liver kinase B‐1/AMPK axis
  Yong Rao, Hong Yu, Lin Gao, Yu‐Ting Lu, Zhao Xu, Hong Liu, Lian‐Quan Gu, Ji‐Ming Ye, Zhi‐Shu Huang
  British Journal of Pharmacology.2017; 174(15): 2457.     CrossRef
• Non-alcoholic fatty liver disease and dyslipidemia: An update
  Niki Katsiki, Dimitri P. Mikhailidis, Christos S. Mantzoros
  Metabolism.2016; 65(8): 1109.     CrossRef
• Exendin-4 Inhibits Hepatic Lipogenesis by Increasing β-Catenin Signaling
  Mi Hae Seo, Jinmi Lee, Seok-Woo Hong, Eun-Jung Rhee, Se Eun Park, Cheol Young Park, Ki Won Oh, Sung Woo Park, Won-Young Lee, Catherine Mounier
  PLOS ONE.2016; 11(12): e0166913.     CrossRef
• The Relationship between Type 2 Diabetes Mellitus and Non-Alcoholic Fatty Liver Disease Measured by Controlled Attenuation Parameter
  Young Eun Chon, Kwang Joon Kim, Kyu Sik Jung, Seung Up Kim, Jun Yong Park, Do Young Kim, Sang Hoon Ahn, Chae Yoon Chon, Jae Bock Chung, Kyeong Hye Park, Ji Cheol Bae, Kwang-Hyub Han
  Yonsei Medical Journal.2016; 57(4): 885.     CrossRef
• The role of the gut microbiota in NAFLD
  Christopher Leung, Leni Rivera, John B. Furness, Peter W. Angus
  Nature Reviews Gastroenterology & Hepatology.2016; 13(7): 412.     CrossRef
• Extrapancreatic effects of incretin hormones: evidence for weight‐independent changes in morphological aspects and oxidative status in insulin‐sensitive organs of the obese nondiabetic Zucker rat (ZFR)
  Ides M. Colin, Henri Colin, Ines Dufour, Charles‐Edouard Gielen, Marie‐Christine Many, Jean Saey, Bernard Knoops, Anne‐Catherine Gérard
  Physiological Reports.2016;[Epub]     CrossRef
• A Guide to Non-Alcoholic Fatty Liver Disease in Childhood and Adolescence
  Jonathan Temple, Paul Cordero, Jiawei Li, Vi Nguyen, Jude Oben
  International Journal of Molecular Sciences.2016; 17(6): 947.     CrossRef
• Extrapancreatic Effect of Glucagon like Peptide-1
  In-Kyung Jeong
  The Korean Journal of Medicine.2015; 89(4): 404.     CrossRef
• Green Tea Extract Rich in Epigallocatechin-3-Gallate Prevents Fatty Liver by AMPK Activation via LKB1 in Mice Fed a High-Fat Diet
  Aline B. Santamarina, Juliana L. Oliveira, Fernanda P. Silva, June Carnier, Laís V. Mennitti, Aline A. Santana, Gabriel H. I. de Souza, Eliane B. Ribeiro, Cláudia M. Oller do Nascimento, Fábio S. Lira, Lila M. Oyama, Patricia Aspichueta
  PLOS ONE.2015; 10(11): e0141227.     CrossRef
• Acarbose, lente carbohydrate, and prebiotics promote metabolic health and longevity by stimulating intestinal production of GLP-1
  Mark F McCarty, James J DiNicolantonio
  Open Heart.2015; 2(1): e000205.     CrossRef
• The Glucagon-Like Peptide-1 Analogue Liraglutide Inhibits Oxidative Stress and Inflammatory Response in the Liver of Rats with Diet-Induced Non-alcoholic Fatty Liver Disease
  Huiting Gao, Zhigang Zeng, Han Zhang, Xiaoli Zhou, Lichang Guan, Weiping Deng, Lishu Xu
  Biological & Pharmaceutical Bulletin.2015; 38(5): 694.     CrossRef
• Glucagon-like polypeptide agonists in type 2 diabetes mellitus: efficacy and tolerability, a balance
  Sri Harsha Tella, Marc S. Rendell
  Therapeutic Advances in Endocrinology and Metabolism.2015; 6(3): 109.     CrossRef
• Gut Microbiota: Association with NAFLD and Metabolic Disturbances
  E. Lau, D. Carvalho, P. Freitas
  BioMed Research International.2015; 2015: 1.     CrossRef
• Nonalcoholic fatty liver disease and bariatric surgery in adolescents
  AiXuan Holterman, Juan Gurria, Smita Tanpure, Nerina DiSomma
  Seminars in Pediatric Surgery.2014; 23(1): 49.     CrossRef
• Pediatric non-alcoholic fatty liver disease: New insights and future directions
  Pierluigi Marzuillo
  World Journal of Hepatology.2014; 6(4): 217.     CrossRef
• 4Ps medicine of the fatty liver: the research model of predictive, preventive, personalized and participatory medicine—recommendations for facing obesity, fatty liver and fibrosis epidemics
  Francesca Maria Trovato, Daniela Catalano, Giuseppe Musumeci, Guglielmo M Trovato
  EPMA Journal.2014;[Epub]     CrossRef
• The Role of Medications for the Management of Patients with NAFLD
  Natalia Mazzella, Laura M. Ricciardi, Arianna Mazzotti, Giulio Marchesini
  Clinics in Liver Disease.2014; 18(1): 73.     CrossRef
• Randomised clinical trial: the beneficial effects of VSL#3 in obese children with non‐alcoholic steatohepatitis
  A. Alisi, G. Bedogni, G. Baviera, V. Giorgio, E. Porro, C. Paris, P. Giammaria, L. Reali, F. Anania, V. Nobili
  Alimentary Pharmacology & Therapeutics.2014; 39(11): 1276.     CrossRef
• The cardiometabolic benefits of glycine: Is glycine an ‘antidote’ to dietary fructose?
  Mark F McCarty, James J DiNicolantonio
  Open Heart.2014; 1(1): e000103.     CrossRef
• Pediatric non-alcoholic fatty liver disease: an increasing public health issue
  S. Berardis, E. Sokal
  European Journal of Pediatrics.2014; 173(2): 131.     CrossRef
• Glucagon‐like peptide‐1 analogue, liraglutide, improves liver fibrosis markers in obese women with polycystic ovary syndrome and nonalcoholic fatty liver disease
  H. Kahal, G. Abouda, A. S. Rigby, A. M. Coady, E. S. Kilpatrick, S. L. Atkin
  Clinical Endocrinology.2014; 81(4): 523.     CrossRef
• Comparative analysis of plasma metabolomics response to metabolic challenge tests in healthy subjects and influence of the FTO obesity risk allele
  Simone Wahl, Susanne Krug, Cornelia Then, Anna Kirchhofer, Gabi Kastenmüller, Tina Brand, Thomas Skurk, Melina Claussnitzer, Cornelia Huth, Margit Heier, Christa Meisinger, Annette Peters, Barbara Thorand, Christian Gieger, Cornelia Prehn, Werner Römisch-
  Metabolomics.2014; 10(3): 386.     CrossRef
• Role of thiazolidinediones, insulin sensitizers, in non‐alcoholic fatty liver disease
  Eugene Chang, Cheol‐Young Park, Sung Woo Park
  Journal of Diabetes Investigation.2013; 4(6): 517.     CrossRef
• Therapeutic options in pediatric non alcoholic fatty liver disease: current status and future directions
  Pietro Vajro, Selvaggia Lenta, Claudio Pignata, Mariacarolina Salerno, Roberta D’Aniello, Ida De Micco, Giulia Paolella, Giancarlo Parenti
  Italian Journal of Pediatrics.2012; 38(1): 55.     CrossRef