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The Regulation of Lipid Metabolism by Targeting Opioid Receptors in Nonalcoholic Fatty Liver Disease

Hsien-Hui Chung

Hsien-Hui Chung, Preventive Medicine Program, Center for General Education, Chung Yuan Christian University, Taoyuan City, Taiwan; Tai-An Medical and Pharmacy Center, Kaohsiung City, Taiwan

Conflict-of-interest statement: The author(s) declare(s) that there is no conflict of interest regarding the publication of this paper.

Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http: //creativecommons.org/licenses/by-nc/4.0/

Correspondence to: Hsien-Hui Chung, PhD, Preventive Medicine Program, Center for General Education, Chung Yuan Christian University, Taoyuan City, Taiwan 32023.
Email: hsienhuichung@yahoo.com.tw
Telephone: +886-91-951-8683

Received: November 6, 2016
Revised: January 31, 2017
Accepted: February 2, 2017
Published online: April 21, 2017

ABSTRACT

Nonalcoholic fatty liver disease (NAFLD) is a well-known hepatic disease without a history of alcohol abuse, which displays a dysfunction of the normal processes of lipid synthesis and elimination in hepatocytes. The chronic endoplasmic reticulum (ER) stress caused by lipid accumulation in hepatocytes interferes with normal cellular function. In addition, inflammation has been thought to be associated with the formation of nonalcoholic steatohepatitis (NASH) and promotes the progression to hepatic fibrosis and liver cirrhosis. Opioid receptors seem to be involved in the regulation of lipid and energy metabolism. Furthermore, the pathogenesis of NAFLD can be improved by the modulation of opioid receptors to attenuate hepatic lipid abnormalities. Thus, the identification of potential compounds by targeting opioid receptors in the improvement of NAFLD is promising.

Key words: Endoplasmic reticulum; Hepatic steatosis; Inflammation; Lipid metabolism; Nonalcoholic fatty liver disease; Nonalcoholic steatohepatitis; Opioid receptor

© 2017 The Author(s). Published by ACT Publishing Group Ltd. All rights reserved.

Chung HH. The Regulation of Lipid Metabolism by Targeting Opioid Receptors in Nonalcoholic Fatty Liver Disease. Journal of Gastroenterology and Hepatology Research 2017; 6(2): 2303-2306 Available from: URL: http: //www.ghrnet.org/index.php/joghr/article/view/1920

INTRODUCTION

Nonalcoholic fatty liver disease (NAFLD) has attracted much attention in the recent years. The clinical diagnosis and evaluation of NAFLD can be diagnosed based on physical examination, illness history, ultrasound examination and hepatic imaging[1]. NAFLD begins as lipid accumulation in the liver (hepatic steatosis), and inflammation can induce the pathogenesis of non-alcoholic steatohepatitis (NASH) that can progress to different degrees of hepatic fibrosis and hepatocellular carcinoma[2]. The pathogenesis of hepatic steatosis is related to lifestyles, dietary habits and environmental factors[3]. Additionally, genetic factors and polymorphisms also contribute to the formation of hepatic steatosis[4]. Moreover, the dysfunction of lipid metabolism in the liver is associated with NAFLD because the increased accumulation of fatty deposition in the liver can initiate a series of inflammatory responses and pathologic changes. Interestingly, opioid receptors and peptides have been thought to play a critical role in the regulation of endocrine metabolism and glucose homeostasis in the past studies[5-7]. However, the effect and mechanism of opioid receptors on the improvement of NAFLD are still unclear. Thus, the review aims to summarize how NAFLD is prevented from further progression by targeting opioid receptors to modulate the lipid metabolism.

THE ROLE OF LIPID METABOLISM WITH INFLAMMATION IN NON-ALCOHOLIC FATTY LIVER DISEASE

Lipids consist of many molecules such as phospholipids, fatty acids, cholesterols, and triglycerides. Hepatic lipid metabolism contains fatty acid synthesis, lipoprotein synthesis and lipid oxidation[8], which is controlled at the genomic levels by multiple regulatory proteins, metabolic enzymes, transcription factors and coregulators, such as fatty acid transport protein (FATP), carbohydrate responsive element binding protein (ChREBP), sterol regulatory element binding protein (SREBP), acetyl-CoA carboxylase (ACC), lipoprotein lipase (LPL), liver X receptor (LXR), farnesoid X receptor (FXR), and peroxisome proliferator-activated receptor (PPAR)[9]. The impairment of lipid metabolism leads to excessive lipid accumulation and triggers inflammatory responses. Some studies have shown that inflammation is involved in many metabolic diseases, including diabetes, hypertension, and NAFLD[10,11]. Inflammation disturbs cellular metabolism and function via the endoplasmic reticulum (ER) stress or oxidative stress, which induces metabolic diseases by interfering with normal glucose and lipid metabolism[12,13]. Inflammatory cytokines can attenuate the sensitivity of metabolic tissues or organs for metabolic hormones by disrupting the signal transduction of glucose and lipid metabolism[14]. Take type 2 diabetes for example, higher levels of inflammatory cytokines [e.g., Interleukin-1 beta (IL-1β), Interleukin-6 (IL-6), Interleukin-18 (IL-18), C-reactive protein (CRP)], tumor necrosis factor (TNF)-α and low levels of adiponectin are closely associated with the induction of insulin resistance[15]. Additionally, the impairment of lipid metabolism via inflammatory response has been reported in NAFLD, and lipotoxicity-induced hepatic injury is characterized by the presence of inflammatory cells in NASH[16]. For the exploration of hepatic lipid metabolism, many animal models have been adopted for the investigation of NAFLD or NASH, including three main types of animal models: (1) Genetic animal models [e.g., SREBP-1c transgenic mice, ob/ob mice, db/db mice and phosphatase and tensin homologue deleted on chromosome 10 (PTEN) null mice]; (2) Nutritional/dietary animal models [e.g., methionine and choline deficiency (MCD) diet, high fat diet (HFD), fructose diet and atherogenic diet]; (3) Combined animal models of genetic modification and dietary factors [e.g., db/db mice fed with MCD diet and PPAR-α null mice fed with MCD diet][17]. Although no animal model can completely exhibit hepatic pathophysiology of NAFLD or NASH in humans, the researchers can select the suitable animal model for their studies according to their experimental design. In summary, the dysfunction of hepatic lipid metabolism with inflammation has a great influence on the development of NAFLD.

THE EFFECT OF OPIOID RECEPTOR ON LIPID AND ENERGY METABOLISM

Opioid receptors belong to inhibitory G protein-coupled receptors. In general, opioid receptors are classified into three subtypes, including mu (μ)- opioid receptors (MOR), kappa (κ)- opioid receptors (KOR) and delta (δ)-opioid receptors (DOR)[18]. In addition, the endogenous opioid peptides contain dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The regulation of opioid receptors with opioid agonists or antagonists can affect many cellular and neuronal signal transductions. Many studies have reported that opioid receptors have beneficial effects on the regulation of glucose metabolism[19, 20]. However, the regulation of opioid receptors on lipid and energy metabolism remains obscure. Cholesterol contributes to opioid receptor signaling via two mechanisms: maintaining the entirety of lipid raft microdomains and directly facilitating opioid receptor signaling[21]. On one hand, the activation of central opioid receptors by selective agonists can stimulate appetite[22]. Interestingly, the stimulation of hypothalamic MOR promotes the preference of HFD[23], and HFD also induces fat accumulation via the higher expression of MOR in the brain suggesting decreased release of endogenous μ-opioid peptides[24,25]. In addition, galanin-induced feeding of HFD is specifically modulated by MOR signaling pathway in sated condition, whereas that is mediated by KOR in starvation[26]. On the other hand, endogenous opioid peptides namely enkephalin and β-endorphin are thought to modulate energy consumption and body weight via targeting MOR and DOR[27,28]. Obesity with increased adiposity and impaired glucose tolerance is resistant in MOR deficient (MOR-/-) mice fed with HFD, which is associated with the activation of metabolic enzymes involved in fatty acid oxidation in skeletal muscle[29]. The long term administration of opioid receptor antagonists can suppress appetite and body weight gain in genetic obese animal models or obese humans[30,31]. The inhibition of opioid receptors by opioid antagonists can improve HFD-induced dyslipidemia[32]. Moreover, the antagonism of opioid receptors can also reduce fat accumulation by the stimulation of lipid utilization and the inhibition of energy intake[33,34]. Thus, the involvement of opioid receptors plays a critical role in lipid and energy metabolism.

THE REGULATION OF OPIOID RECEPTORS IN NON-ALCOHOLIC FATTY LIVER DISEASE

So far, the role of opioid receptors in the improvement of NAFLD has not been clarified. According to the previous report, the hepatic expressions of MOR and DOR but not KOR were present in the rat indicating the distribution difference of opioid receptor subtypes[35]. Some studies have shown that opioid receptors can be potential drug targets in the improvement of liver diseases[36,37]. Opioid signal transduction is upregulated in patients with inflammatory liver disease, and some opioid-like compounds exert immunomodulatory activities to attenuate inflammation[38]. In obese patients with NAFLD, the increased expression of opioid receptors within gastric mucosa is related to the induction of inflammatory cytokines suggesting the effect of opioid receptors on the pathogenesis of NAFLD[39]. The activation of MOR with peripheral MOR agonist can prevent acute hepatic inflammation and cell death induced by hepatotoxin[40]. The overexpression of KOR in lateral hypothalamic area (LHA) can induce hepatic steatosis via parasympathetic nervous system to regulate lipid metabolism, but silencing of KOR expression can abolish hepatic steatosis[41]. The attenuation of KOR expression can decrease hepatic triglyceride synthesis in mice fed with high-energy diet (HED)[42]. In addition, melanin-concentrating hormone (MCH) increases lipid accumulation by the activation of MCH receptors through the parasympathetic nervous system, which promotes the formation of hepatic steatosis[43]. Mice lacking DOR by genetic disruption can decrease hepatic lipid content through the higher expression of adipose triglyceride lipase (ATGL) and increase thermogenesis in brown adipose tissue (BAT) involved in the activation of uncoupling protein 1 (UCP1), peroxisome proliferator-activated receptor gamma coactivator-1 α (PGC1α), and fibroblast growth factor 21 (FGF21)[44,45]. The higher expression of DOR in hepatocellular carcinoma (HCC) is associated with the tumor progression, which can be attenuated by the silencing of DOR[46]. Taken together, the blockade of opioid receptors by genetic silencing or chemical antagonists provides beneficial effects for the impairment of lipid metabolism in NAFLD.

CONCLUSION

In conclusion, the regulation of lipid metabolism by targeting opioid receptors can improve NAFLD and attenuate the progression to NASH and hepatic fibrosis. Therefore, the development of compounds for targeting opioid receptors will be beneficial for the clinical patients with NAFLD.

REFERENCES

1. Cobbold JF, Patel D, Taylor-Robinson SD. Assessment of inflammation and fibrosis in non-alcoholic fatty liver disease by imaging-based techniques. J Gastroenterol Hepatol 2012; 27: 1281-1292 [PMID: 22432836]; [DOI: 10.1111/j.1440-1746.2012.07127.x]

2. Machado MV, Cortez-Pinto H. Non-alcoholic fatty liver disease: what the clinician needs to know. World J Gastroenterol 2014; 20: 12956-12980 [PMID: 25278691]; [DOI: 10.3748/wjg.v20.i36.12956]

3. Satapathy SK, Sanyal AJ. Epidemiology and Natural History of Nonalcoholic Fatty Liver Disease. Semin Lliver Dis 2015; 35: 221-235 [PMID: 26378640]; [DOI: 10.1055/s-0035-1562943]

4. Severson TJ, Besur S, Bonkovsky HL. Genetic factors that affect nonalcoholic fatty liver disease: A systematic clinical review. World J Gastroenterol 2016; 22: 6742-6756 [PMID: 27547017]; [DOI: 10.3748/wjg.v22.i29.6742]

5. Wen T, Peng B, Pintar JE. The MOR-1 opioid receptor regulates glucose homeostasis by modulating insulin secretion. Mol Endocrinol 2009; 23: 671-678 [PMID: 19221053]; [DOI: 10.1210/me.2008-0345]

6. Xia FZ, Lu YL, Chen Y, Gu T, Zhang HX, Yu J, Zhao LJ. Peripheral endomorphin-1 levels are suppressed in diabetic patients. Diabetes Res Clin Pract 2010; 87: 200-203 [PMID: 20022398]; [DOI: 10.1016/j.diabres.2009.11.017]

7. Pfeiffer A, Herz A. Endocrine actions of opioids. Horm Metab Res 1984; 16: 386-397 [PMID: 6088380]; [DOI: 10.1055/s-2007-1014801]

8. Nguyen P, Leray V, Diez M, Serisier S, Le Bloc’h J, Siliart B, Dumon H. Liver lipid metabolism. J Anim Physiol Anim Nutr 2008; 92: 272-283 [PMID: 18477307]; [DOI: 10.1111/j.1439-0396.2007.00752.x]

9. Rui L. Energy metabolism in the liver. Compr Physiol 2014; 4: 177-197 [PMID: 24692138]; [DOI: 10.1002/cphy.c130024]

10. Katsiki N, Mikhailidis DP, Mantzoros CS. Non-alcoholic fatty liver disease and dyslipidemia: An update. Metabolism 2016; 65: 1109-1123 [PMID: 27237577]; [DOI: 10.1016/j.metabol.2016.05.003]

11. Cooke AA, Connaughton RM, Lyons CL, McMorrow AM, Roche HM. Fatty acids and chronic low grade inflammation associated with obesity and the metabolic syndrome. Eur J Pharmacol 2016; 785: 207-214 [PMID: 27083551]; [DOI: 10.1016/j.ejphar.2016.04.021]

12. Bozaykut P, Sahin A, Karademir B, Ozer NK. Endoplasmic reticulum stress related molecular mechanisms in nonalcoholic steatohepatitis. Mech Ageing Dev 2016; 157: 17-29 [PMID: 27393639]; [DOI: 10.1016/j.mad.2016.07.001]

13. Rutkowski DT, Wu J, Back SH, Callaghan MU, Ferris SP, Iqbal J, Clark R, Miao H, Hassler JR, Fornek J, Katze MG, Hussain MM, Song B, Swathirajan J, Wang J, Yau GD, Kaufman RJ. UPR pathways combine to prevent hepatic steatosis caused by ER stress-mediated suppression of transcriptional master regulators. Dev Cell 2008; 15: 829-840 [PMID: 19081072]; [DOI: 10.1016/j.devcel.2008.10.015]

14. Kratz M, Coats BR, Hisert KB, Hagman D, Mutskov V, Peris E, Schoenfelt KQ, Kuzma JN, Larson I, Billing PS, Landerholm RW, Crouthamel M, Gozal D, Hwang S, Singh PK, Becker L. Metabolic dysfunction drives a mechanistically distinct proinflammatory phenotype in adipose tissue macrophages. Cell Metab 2014; 20: 614-625 [PMID: 25242226]; [DOI: 10.1016/j.cmet.2014.08.010]

15. Liu C, Feng X, Li Q, Wang Y, Hua M. Adiponectin, TNF-alpha and inflammatory cytokines and risk of type 2 diabetes: A systematic review and meta-analysis. Cytokine 2016; 86: 100-109 [PMID: 27498215]; [DOI: 10.1016/j.cyto.2016.06.028]

16. Erikci Ertunc M, Hotamisligil GS. Lipid signaling and lipotoxicity in metabolic inflammation: indications for metabolic disease pathogenesis and treatment. J Lipid Res 2016 [PMID: 27330055]; [DOI: 10.1194/jlr.R066514]

17. Takahashi Y, Soejima Y, Fukusato T. Animal models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World J Gastroenterol 2012; 18: 2300-2308 [PMID: 22654421]; [DOI: 10.3748/wjg.v18.i19.2300]

18. Chung HH. The novel role of opioid μ-receptors in gastroenterology. J Gastroenterol Hepatol Res 2013; 2: 614-617 [DOI: 10.6051/j.issn.2224-3992.2013.02.212]

19. Shang Y, Guo F, Li J, Fan R, Ma X, Wang Y, Feng N, Yin Y, Jia M, Zhang S, Zhou J, Wang H, Pei J. Activation of kappa-opioid receptor exerts the glucose-homeostatic effect in streptozotocin-induced diabetic mice. J Cell Biochem 2015; 116: 252-259 [PMID: 25186835]; [DOI: 10.1002/jcb.24962]

20. Gallagher CJ, Gordon CJ, Langefeld CD, Mychaleckyj JC, Freedman BI, Rich SS, Bowden DW, Sale MM. Association of the mu-opioid receptor gene with type 2 diabetes mellitus in an African American population. Mol Genet Metab 2006; 87: 54-60 [PMID: 16140553]; [DOI: 10.1016/j.ymgme.2005.07.013] 21. Zheng H, Zou H, Liu X, Chu J, Zhou Y, Loh HH, Law PY. Cholesterol level influences opioid signaling in cell models and analgesia in mice and humans. J Lipid Res 2012; 53: 1153-1162 [PMID: 22377533]; [DOI: 10.1194/jlr.M024455]

22. Gosnell BA, Levine AS, Morley JE. The stimulation of food intake by selective agonists of mu, kappa and delta opioid receptors. Life Sci 1986; 38: 1081-1088 [PMID: 2870405]

23. Barnes MJ, Holmes G, Primeaux SD, York DA, Bray GA. Increased expression of mu opioid receptors in animals susceptible to diet-induced obesity. Peptides 2006; 27: 3292-3298 [PMID: 16996647]; [DOI: 10.1016/j.peptides.2006.08.008]

24. Smith SL, Harrold JA, Williams G. Diet-induced obesity increases mu opioid receptor binding in specific regions of the rat brain. Brain Res 2002; 953: 215-222 [PMID: 12384255]

25. Barnes MJ, Lapanowski K, Conley A, Rafols JA, Jen KL, Dunbar JC. High fat feeding is associated with increased blood pressure, sympathetic nerve activity and hypothalamic mu opioid receptors. Brain Res Bull 2003; 61: 511-519 [PMID: 13679250]

26. Barton C, York DA, Bray GA. Opioid receptor subtype control of galanin-induced feeding. Peptides 1996; 17: 237-240 [PMID: 8801527]

27. Mendez IA, Ostlund SB, Maidment NT, Murphy NP. Involvement of Endogenous Enkephalins and beta-Endorphin in Feeding and Diet-Induced Obesity. Neuropsychopharmacology 2015; 40: 2103-2112 [PMID: 25754760]; [DOI: 10.1038/npp.2015.67]

28. Reid LD. Endogenous opioid peptides and regulation of drinking and feeding. Am J Clin Nutr 1985; 42: 1099-1132 [PMID: 2865892]

29. Tabarin A, Diz-Chaves Y, Carmona Mdel C, Catargi B, Zorrilla EP, Roberts AJ, Coscina DV, Rousset S, Redonnet A, Parker GC, Inoue K, Ricquier D, Penicaud L, Kieffer BL, Koob GF. Resistance to diet-induced obesity in mu-opioid receptor-deficient mice: evidence for a “thrifty gene”. Diabetes 2005; 54: 3510-3516 [PMID: 16306369]

30. Shaw WN. Long-term treatment of obese Zucker rats with LY255582 and other appetite suppressants. Pharmacol Biochem Behav 1993; 46: 653-659 [PMID: 8278442]

31. Atkinson RL. Naloxone decreases food intake in obese humans. J Clin Endocrinol Metab 1982; 55: 196-198 [PMID: 7042740]; [DOI: 10.1210/jcem-55-1-196]

32. Ibrahim IY, Ibrahim HM, Aziz NM, Rahman DM. The protective role of the opioid antagonist LY255582 in the management of high fat diet-induced obesity in adult male albino rats. Endocr Regul 2015; 49: 198-205 [PMID: 26494038]

33. Statnick MA, Tinsley FC, Eastwood BJ, Suter TM, Mitch CH, Heiman ML. Peptides that regulate food intake: antagonism of opioid receptors reduces body fat in obese rats by decreasing food intake and stimulating lipid utilization. Am J Physiol Regul Integr Comp Physiol 2003; 284: R1399-1408 [PMID: 12736177]; [DOI: 10.1152/ajpregu.00632.2002]

34. Shaw WN, Mitch CH, Leander JD, Mendelsohn LG, Zimmerman DM. The effect of the opioid antagonist LY255582 on body weight of the obese Zucker rat. Int J Obes 1991; 15: 387-395 [PMID: 1653188]

35. Wittert G, Hope P, Pyle D. Tissue distribution of opioid receptor gene expression in the rat. Biochem Biophys Res Commun 1996; 218: 877-881 [PMID: 8579608]; [DOI: 10.1006/bbrc.1996.0156]

36. Kiani S, Ebrahimkhani MR, Shariftabrizi A, Doratotaj B, Payabvash S, Riazi K, Dehghani M, Honar H, Karoon A, Amanlou M, Tavangar SM, Dehpour AR. Opioid system blockade decreases collagenase activity and improves liver injury in a rat model of cholestasis. J Gastroenterol Hepatol 2007; 22: 406-413 [PMID: 17295775]; [DOI: 10.1111/j.1440-1746.2006.04260.x]

37. Jaume M, Jacquet S, Cavailles P, Mace G, Stephan L, Blanpied C, Demur C, Brousset P, Dietrich G. Opioid receptor blockade reduces Fas-induced hepatitis in mice. Hepatology 2004; 40: 1136-1143 [PMID: 15389866]; [DOI: 10.1002/hep.20428]

38. Day SA, Lakner AM, Moore CC, Yen MH, Clemens MG, Wu ES, Schrum LW. Opioid-like compound exerts anti-fibrotic activity via decreased hepatic stellate cell activation and inflammation. Biochem Pharmacol 2011; 81: 996-1003 [PMID: 21291870]; [DOI: 10.1016/j.bcp.2011.01.015]

39. Mehta R, Birerdinc A, Wang L, Younoszai Z, Moazzez A, Elariny H, Goodman Z, Chandhoke V, Baranova A, Younossi ZM. Expression of energy metabolism related genes in the gastric tissue of obese individuals with non-alcoholic fatty liver disease. BMC Gastroenterol 2014; 14: 72 [PMID: 24716593]; [DOI: 10.1186/1471-230X-14-72]

40. Chakass D, Philippe D, Erdual E, Dharancy S, Malapel M, Dubuquoy C, Thuru X, Gay J, Gaveriaux-Ruff C, Dubus P, Mathurin P, Kieffer BL, Desreumaux P, Chamaillard M. micro-Opioid receptor activation prevents acute hepatic inflammation and cell death. Gut 2007; 56: 974-981 [PMID: 17299060]; [DOI: 10.1136/gut.2006.105122]

41. Imbernon M, Sanchez-Rebordelo E, Romero-Pico A, Kallo I, Chee MJ, Porteiro B, Al-Massadi O, Contreras C, Ferno J, Senra A, Gallego R, Folgueira C, Seoane LM, van Gestel M, Adan RA, Liposits Z, Dieguez C, Lopez M, Nogueiras R. Hypothalamic kappa opioid receptor mediates both diet-induced and melanin concentrating hormone-induced liver damage through inflammation and endoplasmic reticulum stress. Hepatology 2016; 64: 1086-1104 [PMID: 27387967]; [DOI: 10.1002/hep.28716]

42. Czyzyk TA, Nogueiras R, Lockwood JF, McKinzie JH, Coskun T, Pintar JE, Hammond C, Tschop MH, Statnick MA. kappa-Opioid receptors control the metabolic response to a high-energy diet in mice. FASEB J 2010; 24: 1151-1159 [PMID: 19917675]; [DOI: 10.1096/fj.09-143610]

43. Imbernon M, Beiroa D, Vazquez MJ, Morgan DA, Veyrat-Durebex C, Porteiro B, Diaz-Arteaga A, Senra A, Busquets S, Velasquez DA, Al-Massadi O, Varela L, Gandara M, Lopez-Soriano FJ, Gallego R, Seoane LM, Argiles JM, Lopez M, Davis RJ, Sabio G, Rohner-Jeanrenaud F, Rahmouni K, Dieguez C, Nogueiras R. Central melanin-concentrating hormone influences liver and adipose metabolism via specific hypothalamic nuclei and efferent autonomic/JNK1 pathways. Gastroenterology 2013; 144: 636-649 e636 [PMID: 23142626]; [DOI: 10.1053/j.gastro.2012.10.051]

44. Czyzyk TA, Romero-Pico A, Pintar J, McKinzie JH, Tschop MH, Statnick MA, Nogueiras R. Mice lacking delta-opioid receptors resist the development of diet-induced obesity. FASEB J 2012; 26: 3483-3492 [PMID: 22593549]; [DOI: 10.1096/fj.12-208041]

45. Zechner R, Kienesberger PC, Haemmerle G, Zimmermann R, Lass A. Adipose triglyceride lipase and the lipolytic catabolism of cellular fat stores. J Lipid Res 2009; 50: 3-21 [PMID: 18952573]; [DOI: 10.1194/jlr.R800031-JLR200]

46. Tang B, Li Y, Yuan S, Tomlinson S, He S. Upregulation of the delta opioid receptor in liver cancer promotes liver cancer progression both in vitro and in vivo. Int J Oncol 2013; 43: 1281-1290 [PMID: 23903826]; [DOI: 10.3892/ijo.2013.2046]

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