P- Reviewer: Gallego-Duran R, Liu HK, Mascitelli L S- Editor: Yu J L- Editor: AmEditor E- Editor: Liu XM
Published online Mar 21, 2015. doi: 10.3748/wjg.v21.i11.3214
Peer-review started: October 20, 2014
First decision: December 11, 2014
Revised: December 29, 2014
Accepted: January 30, 2015
Article in press: January 30, 2015
Published online: March 21, 2015
Nonalcoholic fatty liver disease (NAFLD) is currently considered as the most common liver disease in Western countries, and is rapidly becoming a serious threat to public health worldwide. However, the underlying mechanisms leading to the development of NAFLD are still not fully understood. The ghrelin-ghrelin O-acyltransferase (GOAT) system has recently been found to play a crucial role in both the development of steatosis and its progression to nonalcoholic steatohepatitis. Ghrelin, the natural ligand of the growth hormone secretagogue receptor, is a 28-amino acid peptide possessing a unique acylation on the serine in position 3 catalyzed by GOAT. The ghrelin-GOAT system is involved in insulin resistance, lipid metabolism dysfunction, and inflammation, all of which play important roles in the pathogenesis of NAFLD. A better understanding of ghrelin-GOAT system biology led to the identification of its potential roles in NAFLD. Molecular targets modulating ghrelin-GOAT levels and the biologic effects are being studied, which provide a new insight into the pathogenesis of NAFLD. This review probes into the possible relationship between the ghrelin-GOAT system and NAFLD, and considers the potential mechanisms by which the ghrelin-GOAT system brings about insulin resistance and other aspects concerning NAFLD.
Core tip: Nonalcoholic fatty liver disease (NAFLD) is a progressive disorder that can lead to impaired liver function and, ultimately, liver failure. The ghrelin-ghrelin O-acyltransferase (GOAT) system has recently been found to play a crucial role in both the development of steatosis and its progression to nonalcoholic steatohepatitis. This review probes into the possible relationship between ghrelin-GOAT system and NAFLD, and considers the potential mechanisms by which the ghrelin-GOAT system brings about insulin resistance and other aspects concerning NAFLD.
Citation: Zhang SR, Fan XM. Ghrelin-ghrelin
O-acyltransferase system in the pathogenesis of nonalcoholic fatty liver disease. World J Gastroenterol 2015; 21(11): 3214-3222
- URL: https://www.wjgnet.com/1007-9327/full/v21/i11/3214.htm
- DOI: https://dx.doi.org/10.3748/wjg.v21.i11.3214
Nonalcoholic fatty liver disease (NAFLD) is a metabolic disorder syndrome that is not due to the abuse of alcohol. The term NAFLD encompasses a spectrum of histologically defined liver disorders. The disease can progress from macrovesicular lipid accumulation in the hepatocytes (termed steatosis) to nonalcoholic steatohepatitis (NASH) to outright fibrosis, cirrhosis, and even hepatocellular carcinoma[1-3] (Figure 1). The occurrence of NAFLD is strongly linked to obesity, insulin resistance (IR) and other aspects of the metabolic syndrome.
The reported prevalence of NAFLD in the United States and other Western countries ranges from 30% to 46%[4-6]. This disease has also become prevalent in Eastern countries where it has become a significant public health concern[7,8]. However, patients with NAFLD often have normal liver aminotransferases and the potential presence of NAFLD may be neglected by clinicians[9-12]. Patients with NAFLD are always at high risk for cardiometabolic complications, such as type 2 diabetes (T2DM) and cardiovascular disease[13-16].
The exact pathogenesis of NAFLD remains unknown. A number of environmental and genetic factors are involved in the NAFLD development and progression (Figure 1). The “two-hits hypothesis” is currently the most recognized theory to explain NAFLD development and progression. Fat accumulation in hepatocytes is considered as the primary insult, while the following events, including mitochondrial dysfunction, lipid peroxidation, IR, and oxidative stress, result in liver cell inflammation and apoptosis, which eventually progress from simple steatosis to NASH[18-20]. Although the “two-hits hypothesis” of NAFLD pathogenesis is currently the most recognized theory, the “multi-hits hypothesis” that involves lipotoxicity, oxidative stress, mitochondrial dysfunction, a chronic inflammatory state, and endoplasmic reticulum stress, is getting more and more attention. The “multi-hits hypothesis” summarizes the complex factors and interactions between cytokines, free fatty acids (FFAs) metabolism, inflammation, and IR in NAFLD[21,22].
As oxidative stress and inflammation are key events in the progression from simple steatosis to NASH, retardation of these processes may reverse the development of NAFLD[18,20]. Thus, use of low side-effect agents that ameliorate those key events of NAFLD may provide important therapeutic evidence for the development of NAFLD. In recent years, a number of chemical agents have been found to have protective efficacy against NAFLD-induced liver injury, oxidative stress, and inflammation[23-26].
Recently, several studies have shown some advances in the pathogenesis of NAFLD. Advances in the understanding of autophagy have provided insights into the relationship between autophagy and NAFLD. Autophagy might stimulate lipid metabolism and have therapeutic potential in NAFLD. Helicobacter pylori infection is involved in the pathogenesis of IR, which is closely linked with NAFLD. The role of H. pylori infection in the development of NAFLD is gaining attention because its eradication is easy and much less expensive than long-term treatment of the other risk factors. Besides, overexpression of miR-185, an endogenous non-protein coding small RNA molecule, improved insulin sensitivity and reduced liver steatosis in an NAFLD animal model, and thus may be a therapeutic target. In recent years, several adipocytokines and proinflammatory cytokines, which decrease or enhance IR, were also found to be involved in the pathogenesis of NAFLD[30-32]. Nevertheless, the complicated mechanisms of NAFLD are not entirely clear at present. Future better-designed research will provide more insights into the pathogenesis and therapeutic strategies for NAFLD.
The ghrelin-ghrelin O-acyltransferase (GOAT) system has recently been reported to play a crucial role in both the development of steatosis and progression to NASH. The ghrelin-GOAT system is involved in IR, lipid metabolism dysfunction, and inflammation, all of which play important roles in the pathogenesis of NAFLD[33-36]. Therefore, there is an urgent need to better understand the mechanisms of ghrelin-GOAT system involvement in NAFLD. This review will illuminate the relationship between the ghrelin-GOAT system and pathogenesis of NAFLD.
Ghrelin is a small peptide and hormone comprised of 28 amino acids that is mainly produced by the stomach and the pancreas, which stimulates appetite and is a potent stimulator of growth hormone through the action of its receptor, the growth horomone secretagogue receptor[38,39]. A number of studies have shown that exogenous administration of ghrelin produces multiple physiologic effects, including the ability to increase food intake and decrease energy expenditure[38,40]. Ghrelin undergoes a post-translational modification, in which the third serine residue is covalently linked to a medium-chain fatty acid, typically octanoate. The O-n-octanoylation of ghrelin is unique, and only the octanoylated form, which represents 10%-15% of circulating ghrelin, is able to stimulate body weight gain and food intake[42,43].
There are two forms of ghrelin: acylated and des-acyl ghrelin (DAG). Without food intake, both forms rise gradually in the plasma. Although some effects of DAG are still controversial and its receptor has not been identified, the biologic activities of DAG have been reported, including gastric motility[44,45], adiposity, and glucose metabolism. Further evidence for metabolic function of ghrelin has been provided by phenotypic analysis of rodents with genetic deletions of either ghrelin or its receptor, GHS-R1a.
Ghrelin is acylated on the serine in position 3. Both forms of ghrelin may result from the processing of preproghrelin. The acylation is catalyzed by GOAT during the processing of the peptide[29,50]. Ingestion of either medium-chain fatty acids or medium-chain triglycerides can enhance acylation of ghrelin.
Lim et al found that GOAT is expressed in all human tissues studied (stomach, adrenal cortex, breast, and right and left colon). The widespread expression of GOAT corresponds to the widespread distribution of ghrelin expression. GOAT expression was high in the stomach and gut, the major ghrelin-secreting tissues, and in the pituitary, ghrelin showed autocrine and paracrine effects. In addition to the important endocrine effects of acylated ghrelin, the paracrine effects of locally synthesized and acylated ghrelin may also be important. The concept was supported by the identification of GOAT expression in various tissues. It will be helpful to search for GOAT inhibitors as an alternative approach to reduce the actions of ghrelin, such as feeding and adiposity. As the action of GOAT and its inhibition are very specific to ghrelin, this may be a promising therapeutic target.
The activity of GOAT is modulated by fasting and satiation[53-55]. Although feeding suppresses both acylated ghrelin and DAG, long-term fasting inhibits ghrelin acylation but not total ghrelin secretion. The exact effect of fasting and feeding on GOAT mRNA expression remains vague[57,58]. GOAT has been confirmed as a leptin-regulated gene, and González et al found that exogenous leptin administration markedly increased GOAT mRNA levels in the gastric mucosa of fasted rats. It has been indicated that fasting low-leptin levels prevent an increase in GOAT mRNA levels, and therefore, GOAT can be added to the list of leptin-regulated genes under this specific condition. Leptin is the primary signal through which the hypothalamus senses the nutritional state and modulates food intake and energy balance. Leptin plays an opposite functional role of ghrelin in food intake and it also regulates ghrelin receptor GHS-R1a[59,60]. Increased GOAT mRNA levels relevant to chronic malnutrition may elucidate the potential mechanism responsible for increased acylated ghrelin levels in anorexia nervosa.
Alimentary lipids are important for the activation of GOAT. In fact, GOAT knockout mice subjected to a diet containing 10% medium-chain triglycerides exhibited lower body weights, possibly due to lower fat mass, compared to wild-type mice. In addition, large amounts of acyl ghrelin were produced by GOAT transgenic mice. An important function of ghrelin is the maintenance of viability during famine. The study of wild-type and GOAT knockout mice subjected to a 60% calorie-restricted diet showed 30% and 75% body weight loss, respectively, which could explain this hypothesis.
The ghrelin-GOAT system is linked to energy and lipid metabolism, IR, inflammation, and apoptotic cell death, which are common to both obesity and NAFLD. Therefore, the role of the ghrelin-GOAT system in NAFLD has become a subject of considerable interest in recent years.
The relation of the ghrelin gene products and their involvement in metabolic and inflammatory pathways linked with the development of NAFLD were recently reported. It was found that patients with NASH had a twofold higher concentration of DAG than patients with non-NASH. Ghrelin concentration positively correlated with fibrosis stage. Apparently, products of the ghrelin gene may be important for the pathogenesis of NASH and fibrosis. The report by Li et al showed that both administration of ghrelin during the induction of NAFLD and after the establishment of NAFLD could improve liver injury via attenuating alanine aminotransferase/aspartate transaminase, oxidative stress, inflammation, apoptosis, and restoring hepatic lipid metabolism. Such effects might partly act through targeting the PI3K/Akt and LKB1/AMPK pathways. Therefore, ghrelin can be a critical therapeutic agent against NAFLD. However, other research yielded different results. One study reported that the plasma levels of ghrelin in obese individuals were lower than those in normal-weight people, indicating that ghrelin may not be related to the progression of obesity.
The role of ghrelin in appetite regulation and energy metabolism is well established and it is now recognized as a very promising target for the treatment of NAFLD. GHS-R antagonists and ghrelin antibodies are being studied in these systems. An anti-obesity vaccine that prevents ghrelin from reaching the central nervous system has been developed. A glucagon-like peptide-1 receptor agonist, exendin-4, has shown the effect of inhibiting ghrelin secretion.
Besides ghrelin and GHS-R, GOAT has also been implicated as a potential target for anti-NAFLD treatment[35,36]. GOAT inhibition will lead to decreased ghrelin acylation and increased levels of DAG, which is suggested to be beneficial for glucose homeostasis[68,69]. At the moment, there are no anti-NAFLD drugs on the market that target the ghrelin system. This is mainly due to the variation or lack of efficacy, potency, non-selectivity, poor bioavailability, sustained weight loss, and/or adverse side effects. However, specific antagonists are being developed and their relevance to clinical practice is being studied.
IR is a disorder in insulin signaling in many organs, including the liver, fat, and muscle, and is a major characteristic of obesity, T2DM, and NAFLD. IR is an essential requirement for NAFLD and is believed to influence “the first hit” in NAFLD. Some research has illuminated that IR is a typical character of NAFLD[70-73]. NAFLD is highly prevalent among patients with T2DM. By addressing NAFLD both as a consequence and as a cause of IR through lessons learned from the liver of patients with T2DM, Takamura et al presented the remarkable changes in the liver in NAFLD. The development of NAFLD appears to be associated with food intake, as diet is an important contributor to its pathogenesis.
In recent years, ghrelin has been found to play a direct role in glucose homeostasis. A number of reports have demonstrated ghrelin expression in pancreatic islets[77-80] and the ability of ghrelin to regulate insulin secretion and promote β-cell proliferation and survival[81,82]. However, the role of ghrelin in the secretion and action of insulin remains controversial. Some studies show that ghrelin increases insulin secretion[79,81,83-85], whereas other reports show that it inhibits it[86-89].
Mice genetically deficient in the GOAT enzyme lack acylated ghrelin and exhibit a modest decrease in body weight and fat mass when fed a diet rich in medium-chain triglycerides. When these mice were subjected to a period of severe caloric restriction, they were unable to maintain normal blood glucose levels, resulting in eventual death, unless either ghrelin or growth hormone was provided. A recent report showed that a GOAT-specific acyltransferase inhibitor could improve glucose tolerance and reduce weight gain, indicating the effect of the ghrelin-GOAT system on glucose homeostasis.
IR patients with NAFLD show decreased insulin sensitivity not only in muscle, but also in liver and adipose tissue[73,91]. The adipose tissue becomes resistant to the anti-lipolytic effect of insulin, and the release of fatty acids is increased in IR. An important source of FFAs is the increased spillover from chylomicrons under postprandial conditions. It was supposed that ectopic fat may be a defense mechanism against lipotoxicity[94,95], and that patients with NAFLD develop NASH and cirrhosis only after a second hit. Therefore, it is not surprising that gut hormones that are known to control the uptake of nutrients by organs are now increasingly investigated in NAFLD.
The first step in the development of NAFLD is hepatic steatosis, which is characterized by macrovesicular accumulation of triglycerides in the cytoplasm of hepatocytes. Sources of increased hepatic lipids in NAFLD include excess dietary chylomicron remnants, increased new lipogenesis, or excess FFAs released from the lipolysis of adipose tissue[96-98]. Saturated fat seems to stimulate hepatic lipid accumulation and progression into NASH, whereas unsaturated fat, choline, antioxidants, and high-protein diets rich in isoflavones seem to have a more preventive effect. Li et al recently found that ghrelin activated hepatocyte lipogenesis via the mTOR-PPARγ signaling pathway; ghrelin-induced lipogenesis was mediated by mTOR, and the effect was significantly attenuated by PPARγ antagonism in cultured hepatocytes and in PPARγ-deficient mice.
Lipid accumulation within the liver represents an equilibrium between synthesis and utilization. The indiscriminate lipid metabolism and increased lipid flux through the liver result in intracellular stress, apoptosis, and consequent liver damage. IR in adipose tissue with uncontrolled lipolysis resulting in enhanced FFA delivery to the liver has been postulated to be a critical factor in development of NAFLD. IR in adipose tissue has been shown to correlate with severity of liver biopsy findings in NASH. Adipose tissue tumor necrosis factor (TNF)-α and circulating interleukin 6 are associated with IR and circulating FFA levels, and both are increased in patients with NAFLD[102-104]. It is entirely plausible that endocrine abnormalities with hormonal excess and deficiencies may be implicated in the pathogenesis of NAFLD.
Ghrelin stimulates food intake and decreases energy expenditure in rats[48,105-108]. Ghrelin also increases appetite and stimulates food intake in humans. A recent study evaluated ghrelin levels and their relationship with NAFLD and IR in obese adolescents, and found that ghrelin was negatively correlated with weight. Ghrelin concentrations decrease with weight gain resulting from overfeeding, pregnancy, or olanzapine treatment[110-113]. Indeed, ghrelin stimulates the gene expression of lipogenic enzymes, such as acetyl CoA carboxylase, stearoyl CoA desaturase, and fatty acid synthase in white adipose tissue.
In order to determine GOAT expression and functional regulation, measurement of its protein levels and activity will be critical. Recently, genetic variation in GOAT was found in association with anorexia nervosa, though whether it may also be involved in NAFLD remains unknown. Inhibition of GOAT by a peptide-based bisubstrate analog (GO-CoA-Tat) reduced weight gain and improved glucose tolerance in wild-type mice. In fact, GOAT is the only enzyme responsible for ghrelin acylation and its alteration will only affect the physiologic process of ghrelin acylation. In the future, special medicine targeting GOAT may be designed as a novel therapeutic approach for NAFLD.
A small portion of patients with NAFLD will develop inflammation and fibrosis, termed NASH, which is a more progressive, inflammatory disease phenotype of NAFLD. In recent years, the roles of ghrelin in immunity regulation under inflammatory conditions and liver protection have been being clarified. In the gastrointestinal tract, administration of exogenous ghrelin ameliorates the release of proinflammatory cytokines, promotes cell proliferation, and reduces apoptosis after TNF-α- or lipopolysaccharide-induced inflammation. Administration of ghrelin has therapeutic effects for several inflammatory diseases in rodent models, including sepsis, intestinal ischemia and reperfusion injury, pancreatic disease, cardiovascular disease, and gastrointestinal disease. In addition, a recent study demonstrated that pretreatment with ghrelin prior to carbon tetrachloride intoxication attenuated liver injury and oxidative stress. Thus, inflammation represents an important mechanism for the development of NAFLD to NASH. Now that recent research has suggested the anti-inflammatory role of ghrelin in many organs, it is possible that future study will identify its pharmacologic role in the development of NAFLD.
NAFLD is becoming a serious threat to public health worldwide. However, the underlying mechanisms leading to the development of NAFLD are not fully understood. The involvement of the ghrelin-GOAT system in NAFLD and a better understanding of its biology have led to the identification of pharmacologic targets and the development of pharmacologic compounds for the treatment of NAFLD and related diseases. Thus, the ghrelin-GOAT system represents a promising target for the treatment of NAFLD.
|1.||Dowman JK, Tomlinson JW, Newsome PN. Systematic review: the diagnosis and staging of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2011;33:525-540. [PubMed] [DOI]|
|2.||Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology. 1999;116:1413-1419. [PubMed] [DOI]|
|3.||Bugianesi E, Leone N, Vanni E, Marchesini G, Brunello F, Carucci P, Musso A, De Paolis P, Capussotti L, Salizzoni M. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology. 2002;123:134-140. [PubMed] [DOI]|
|4.||Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, Charlton M, Sanyal AJ. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology. 2012;142:1592-1609. [PubMed] [DOI]|
|5.||Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M, Landt CL, Harrison SA. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology. 2011;140:124-131. [PubMed] [DOI]|
|6.||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. [PubMed] [DOI]|
|7.||Fan JG. Epidemiology of alcoholic and nonalcoholic fatty liver disease in China. J Gastroenterol Hepatol. 2013;28 Suppl 1:11-17. [PubMed] [DOI]|
|8.||Farrell GC, Wong VW, Chitturi S. NAFLD in Asia--as common and important as in the West. Nat Rev Gastroenterol Hepatol. 2013;10:307-318. [PubMed]|
|9.||Fracanzani AL, Valenti L, Bugianesi E, Andreoletti M, Colli A, Vanni E, Bertelli C, Fatta E, Bignamini D, Marchesini G. Risk of severe liver disease in nonalcoholic fatty liver disease with normal aminotransferase levels: a role for insulin resistance and diabetes. Hepatology. 2008;48:792-798. [PubMed] [DOI]|
|10.||Kotronen A, Juurinen L, Hakkarainen A, Westerbacka J, Cornér A, Bergholm R, Yki-Järvinen H. Liver fat is increased in type 2 diabetic patients and underestimated by serum alanine aminotransferase compared with equally obese nondiabetic subjects. Diabetes Care. 2008;31:165-169. [PubMed] [DOI]|
|11.||Gastaldelli A, Cusi K, Pettiti M, Hardies J, Miyazaki Y, Berria R, Buzzigoli E, Sironi AM, Cersosimo E, Ferrannini E. Relationship between hepatic/visceral fat and hepatic insulin resistance in nondiabetic and type 2 diabetic subjects. Gastroenterology. 2007;133:496-506. [PubMed] [DOI]|
|12.||Bellentani S, Saccoccio G, Masutti F, Crocè LS, Brandi G, Sasso F, Cristanini G, Tiribelli C. Prevalence of and risk factors for hepatic steatosis in Northern Italy. Ann Intern Med. 2000;132:112-117. [PubMed] [DOI]|
|13.||Bhatia LS, Curzen NP, Calder PC, Byrne CD. Non-alcoholic fatty liver disease: a new and important cardiovascular risk factor? Eur Heart J. 2012;33:1190-1200. [PubMed] [DOI]|
|14.||Targher G, Day CP, Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med. 2010;363:1341-1350. [PubMed]|
|15.||Targher G, Byrne CD. Clinical Review: Nonalcoholic fatty liver disease: a novel cardiometabolic risk factor for type 2 diabetes and its complications. J Clin Endocrinol Metab. 2013;98:483-495. [PubMed] [DOI]|
|16.||Fabbrini E, Sullivan S, Klein S. Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications. Hepatology. 2010;51:679-689. [PubMed] [DOI]|
|17.||Day CP, James OF. Steatohepatitis: a tale of two “hits”? Gastroenterology. 1998;114:842-845. [PubMed] [DOI]|
|18.||Harmon RC, Tiniakos DG, Argo CK. Inflammation in nonalcoholic steatohepatitis. Expert Rev Gastroenterol Hepatol. 2011;5:189-200. [PubMed] [DOI]|
|19.||Alkhouri N, Carter-Kent C, Feldstein AE. Apoptosis in nonalcoholic fatty liver disease: diagnostic and therapeutic implications. Expert Rev Gastroenterol Hepatol. 2011;5:201-212. [PubMed] [DOI]|
|20.||Koek GH, Liedorp PR, Bast A. The role of oxidative stress in non-alcoholic steatohepatitis. Clin Chim Acta. 2011;412:1297-1305. [PubMed] [DOI]|
|21.||Polyzos SA, Kountouras J, Zavos C. Nonalcoholic fatty liver disease: the pathogenetic roles of insulin resistance and adipocytokines. Curr Mol Med. 2009;9:299-314. [PubMed] [DOI]|
|22.||Liu J, Xu Y, Hu Y, Wang G. The role of fibroblast growth factor 21 in the pathogenesis of non-alcoholic fatty liver disease and implications for therapy. Metabolism. 2015;64:380-390. [PubMed] [DOI]|
|23.||Pan M, Song YL, Xu JM, Gan HZ. Melatonin ameliorates nonalcoholic fatty liver induced by high-fat diet in rats. J Pineal Res. 2006;41:79-84. [PubMed] [DOI]|
|24.||Panchal SK, Poudyal H, Arumugam TV, Brown L. Rutin attenuates metabolic changes, nonalcoholic steatohepatitis, and cardiovascular remodeling in high-carbohydrate, high-fat diet-fed rats. J Nutr. 2011;141:1062-1069. [PubMed] [DOI]|
|25.||Song Z, Deaciuc I, Zhou Z, Song M, Chen T, Hill D, McClain CJ. Involvement of AMP-activated protein kinase in beneficial effects of betaine on high-sucrose diet-induced hepatic steatosis. Am J Physiol Gastrointest Liver Physiol. 2007;293:G894-G902. [PubMed] [DOI]|
|26.||Park HJ, DiNatale DA, Chung MY, Park YK, Lee JY, Koo SI, O’Connor M, Manautou JE, Bruno RS. Green tea extract attenuates hepatic steatosis by decreasing adipose lipogenesis and enhancing hepatic antioxidant defenses in ob/ob mice. J Nutr Biochem. 2011;22:393-400. [PubMed] [DOI]|
|27.||Sinha RA, Farah BL, Singh BK, Siddique MM, Li Y, Wu Y, Ilkayeva OR, Gooding J, Ching J, Zhou J. Caffeine stimulates hepatic lipid metabolism by the autophagy-lysosomal pathway in mice. Hepatology. 2014;59:1366-1380. [PubMed] [DOI]|
|28.||Li M, Shen Z, Li YM. Potential role of Helicobacter pylori infection in nonalcoholic fatty liver disease. World J Gastroenterol. 2013;19:7024-7031. [PubMed] [DOI]|
|29.||Wang XC, Zhan XR, Li XY, Yu JJ, Liu XM. MicroRNA-185 regulates expression of lipid metabolism genes and improves insulin sensitivity in mice with non-alcoholic fatty liver disease. World J Gastroenterol. 2014;20:17914-17923. [PubMed] [DOI]|
|30.||El-Wakkad A, Hassan Nel-M, Sibaii H, El-Zayat SR. Proinflammatory, anti-inflammatory cytokines and adiponkines in students with central obesity. Cytokine. 2013;61:682-687. [PubMed] [DOI]|
|31.||Zuo H, Shi Z, Yuan B, Dai Y, Wu G, Hussain A. Association between serum leptin concentrations and insulin resistance: a population-based study from China. PLoS One. 2013;8:e54615. [PubMed] [DOI]|
|32.||Ozcelik F, Yuksel C, Arslan E, Genc S, Omer B, Serdar MA. Relationship between visceral adipose tissue and adiponectin, inflammatory markers and thyroid hormones in obese males with hepatosteatosis and insulin resistance. Arch Med Res. 2013;44:273-280. [PubMed] [DOI]|
|33.||Li Y, Hai J, Li L, Chen X, Peng H, Cao M, Zhang Q. Administration of ghrelin improves inflammation, oxidative stress, and apoptosis during and after non-alcoholic fatty liver disease development. Endocrine. 2013;43:376-386. [PubMed] [DOI]|
|34.||Estep M, Abawi M, Jarrar M, Wang L, Stepanova M, Elariny H, Moazez A, Goodman Z, Chandhoke V, Baranova A. Association of obestatin, ghrelin, and inflammatory cytokines in obese patients with non-alcoholic fatty liver disease. Obes Surg. 2011;21:1750-1757. [PubMed] [DOI]|
|35.||Yang J, Brown MS, Liang G, Grishin NV, Goldstein JL. Identification of the acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide hormone. Cell. 2008;132:387-396. [PubMed] [DOI]|
|36.||Gualillo O, Lago F, Dieguez C. Introducing GOAT: a target for obesity and anti-diabetic drugs? Trends Pharmacol Sci. 2008;29:398-401. [PubMed] [DOI]|
|37.||Inui A, Asakawa A, Bowers CY, Mantovani G, Laviano A, Meguid MM, Fujimiya M. Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endocrine organ. FASEB J. 2004;18:439-456. [PubMed] [DOI]|
|38.||Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402:656-660. [PubMed] [DOI]|
|39.||Castañeda TR, Tong J, Datta R, Culler M, Tschöp MH. Ghrelin in the regulation of body weight and metabolism. Front Neuroendocrinol. 2010;31:44-60. [PubMed] [DOI]|
|40.||Wren AM, Small CJ, Abbott CR, Dhillo WS, Seal LJ, Cohen MA, Batterham RL, Taheri S, Stanley SA, Ghatei MA. Ghrelin causes hyperphagia and obesity in rats. Diabetes. 2001;50:2540-2547. [PubMed] [DOI]|
|41.||Banks WA, Tschöp M, Robinson SM, Heiman ML. Extent and direction of ghrelin transport across the blood-brain barrier is determined by its unique primary structure. J Pharmacol Exp Ther. 2002;302:822-827. [PubMed] [DOI]|
|42.||Tschöp M, Smiley DL, Heiman ML. Ghrelin induces adiposity in rodents. Nature. 2000;407:908-913. [PubMed] [DOI]|
|43.||Akamizu T, Takaya K, Irako T, Hosoda H, Teramukai S, Matsuyama A, Tada H, Miura K, Shimizu A, Fukushima M. Pharmacokinetics, safety, and endocrine and appetite effects of ghrelin administration in young healthy subjects. Eur J Endocrinol. 2004;150:447-455. [PubMed] [DOI]|
|44.||Chen CY, Inui A, Asakawa A, Fujino K, Kato I, Chen CC, Ueno N, Fujimiya M. Des-acyl ghrelin acts by CRF type 2 receptors to disrupt fasted stomach motility in conscious rats. Gastroenterology. 2005;129:8-25. [PubMed] [DOI]|
|45.||Toshinai K, Yamaguchi H, Sun Y, Smith RG, Yamanaka A, Sakurai T, Date Y, Mondal MS, Shimbara T, Kawagoe T. Des-acyl ghrelin induces food intake by a mechanism independent of the growth hormone secretagogue receptor. Endocrinology. 2006;147:2306-2314. [PubMed] [DOI]|
|46.||Zhang W, Chai B, Li JY, Wang H, Mulholland MW. Effect of des-acyl ghrelin on adiposity and glucose metabolism. Endocrinology. 2008;149:4710-4716. [PubMed] [DOI]|
|47.||Wortley KE, del Rincon JP, Murray JD, Garcia K, Iida K, Thorner MO, Sleeman MW. Absence of ghrelin protects against early-onset obesity. J Clin Invest. 2005;115:3573-3578. [PubMed] [DOI]|
|48.||Zigman JM, Nakano Y, Coppari R, Balthasar N, Marcus JN, Lee CE, Jones JE, Deysher AE, Waxman AR, White RD. Mice lacking ghrelin receptors resist the development of diet-induced obesity. J Clin Invest. 2005;115:3564-3572. [PubMed] [DOI]|
|49.||Hosoda H, Kojima M, Mizushima T, Shimizu S, Kangawa K. Structural divergence of human ghrelin. Identification of multiple ghrelin-derived molecules produced by post-translational processing. J Biol Chem. 2003;278:64-70. [PubMed] [DOI]|
|50.||Gutierrez JA, Solenberg PJ, Perkins DR, Willency JA, Knierman MD, Jin Z, Witcher DR, Luo S, Onyia JE, Hale JE. Ghrelin octanoylation mediated by an orphan lipid transferase. Proc Natl Acad Sci USA. 2008;105:6320-6325. [PubMed] [DOI]|
|51.||Nishi Y, Hiejima H, Hosoda H, Kaiya H, Mori K, Fukue Y, Yanase T, Nawata H, Kangawa K, Kojima M. Ingested medium-chain fatty acids are directly utilized for the acyl modification of ghrelin. Endocrinology. 2005;146:2255-2264. [PubMed] [DOI]|
|52.||Lim CT, Kola B, Grossman A, Korbonits M. The expression of ghrelin O-acyltransferase (GOAT) in human tissues. Endocr J. 2011;58:707-710. [PubMed] [DOI]|
|53.||Cummings DE, Purnell JQ, Frayo RS, Schmidova K, Wisse BE, Weigle DS. A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes. 2001;50:1714-1719. [PubMed] [DOI]|
|54.||Cummings DE. Ghrelin and the short- and long-term regulation of appetite and body weight. Physiol Behav. 2006;89:71-84. [PubMed] [DOI]|
|55.||Tschöp M, Wawarta R, Riepl RL, Friedrich S, Bidlingmaier M, Landgraf R, Folwaczny C. Post-prandial decrease of circulating human ghrelin levels. J Endocrinol Invest. 2001;24:RC19-RC21. [PubMed] [DOI]|
|56.||Liu J, Prudom CE, Nass R, Pezzoli SS, Oliveri MC, Johnson ML, Veldhuis P, Gordon DA, Howard AD, Witcher DR. Novel ghrelin assays provide evidence for independent regulation of ghrelin acylation and secretion in healthy young men. J Clin Endocrinol Metab. 2008;93:1980-1987. [PubMed] [DOI]|
|57.||Kirchner H, Gutierrez JA, Solenberg PJ, Pfluger PT, Czyzyk TA, Willency JA, Schürmann A, Joost HG, Jandacek RJ, Hale JE. GOAT links dietary lipids with the endocrine control of energy balance. Nat Med. 2009;15:741-745. [PubMed] [DOI]|
|58.||González CR, Vázquez MJ, López M, Diéguez C. Influence of chronic undernutrition and leptin on GOAT mRNA levels in rat stomach mucosa. J Mol Endocrinol. 2008;41:415-421. [PubMed] [DOI]|
|59.||Nogueiras R, Tovar S, Mitchell SE, Rayner DV, Archer ZA, Dieguez C, Williams LM. Regulation of growth hormone secretagogue receptor gene expression in the arcuate nuclei of the rat by leptin and ghrelin. Diabetes. 2004;53:2552-2558. [PubMed] [DOI]|
|60.||López M, Tovar S, Vázquez MJ, Williams LM, Diéguez C. Peripheral tissue-brain interactions in the regulation of food intake. Proc Nutr Soc. 2007;66:131-155. [PubMed] [DOI]|
|61.||Soriano-Guillén L, Barrios V, Campos-Barros A, Argente J. Ghrelin levels in obesity and anorexia nervosa: effect of weight reduction or recuperation. J Pediatr. 2004;144:36-42. [PubMed] [DOI]|
|62.||Zhao TJ, Liang G, Li RL, Xie X, Sleeman MW, Murphy AJ, Valenzuela DM, Yancopoulos GD, Goldstein JL, Brown MS. Ghrelin O-acyltransferase (GOAT) is essential for growth hormone-mediated survival of calorie-restricted mice. Proc Natl Acad Sci USA. 2010;107:7467-7472. [PubMed] [DOI]|
|63.||Cummings DE, Weigle DS, Frayo RS, Breen PA, Ma MK, Dellinger EP, Purnell JQ. Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med. 2002;346:1623-1630. [PubMed] [DOI]|
|64.||Soares JB, Roncon-Albuquerque R, Leite-Moreira A. Ghrelin and ghrelin receptor inhibitors: agents in the treatment of obesity. Expert Opin Ther Targets. 2008;12:1177-1189. [PubMed] [DOI]|
|65.||Schellekens H, Dinan TG, Cryan JF. Lean mean fat reducing “ghrelin” machine: hypothalamic ghrelin and ghrelin receptors as therapeutic targets in obesity. Neuropharmacology. 2010;58:2-16. [PubMed] [DOI]|
|66.||Zorrilla EP, Iwasaki S, Moss JA, Chang J, Otsuji J, Inoue K, Meijler MM, Janda KD. Vaccination against weight gain. Proc Natl Acad Sci USA. 2006;103:13226-13231. [PubMed] [DOI]|
|67.||Pérez-Tilve D, González-Matías L, Alvarez-Crespo M, Leiras R, Tovar S, Diéguez C, Mallo F. Exendin-4 potently decreases ghrelin levels in fasting rats. Diabetes. 2007;56:143-151. [PubMed] [DOI]|
|68.||Ariyasu H, Takaya K, Iwakura H, Hosoda H, Akamizu T, Arai Y, Kangawa K, Nakao K. Transgenic mice overexpressing des-acyl ghrelin show small phenotype. Endocrinology. 2005;146:355-364. [PubMed] [DOI]|
|69.||Iwakura H, Hosoda K, Son C, Fujikura J, Tomita T, Noguchi M, Ariyasu H, Takaya K, Masuzaki H, Ogawa Y. Analysis of rat insulin II promoter-ghrelin transgenic mice and rat glucagon promoter-ghrelin transgenic mice. J Biol Chem. 2005;280:15247-15256. [PubMed] [DOI]|
|70.||Sanyal AJ, Campbell-Sargent C, Mirshahi F, Rizzo WB, Contos MJ, Sterling RK, Luketic VA, Shiffman ML, Clore JN. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology. 2001;120:1183-1192. [PubMed] [DOI]|
|71.||Yki-Järvinen H. Liver fat in the pathogenesis of insulin resistance and type 2 diabetes. Dig Dis. 2010;28:203-209. [PubMed] [DOI]|
|72.||Fabbrini E, Magkos F, Mohammed BS, Pietka T, Abumrad NA, Patterson BW, Okunade A, Klein S. Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity. Proc Natl Acad Sci USA. 2009;106:15430-15435. [PubMed] [DOI]|
|73.||Bugianesi E, Gastaldelli A, Vanni E, Gambino R, Cassader M, Baldi S, Ponti V, Pagano G, Ferrannini E, Rizzetto M. Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms. Diabetologia. 2005;48:634-642. [PubMed] [DOI]|
|74.||Targher G, Bertolini L, Padovani R, Rodella S, Tessari R, Zenari L, Day C, Arcaro G. Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients. Diabetes Care. 2007;30:1212-1218. [PubMed] [DOI]|
|75.||Takamura T, Misu H, Ota T, Kaneko S. Fatty liver as a consequence and cause of insulin resistance: lessons from type 2 diabetic liver. Endocr J. 2012;59:745-763. [PubMed] [DOI]|
|76.||de Wit NJ, Afman LA, Mensink M, Müller M. Phenotyping the effect of diet on non-alcoholic fatty liver disease. J Hepatol. 2012;57:1370-1373. [PubMed] [DOI]|
|77.||Date Y, Nakazato M, Hashiguchi S, Dezaki K, Mondal MS, Hosoda H, Kojima M, Kangawa K, Arima T, Matsuo H. Ghrelin is present in pancreatic alpha-cells of humans and rats and stimulates insulin secretion. Diabetes. 2002;51:124-129. [PubMed] [DOI]|
|78.||Prado CL, Pugh-Bernard AE, Elghazi L, Sosa-Pineda B, Sussel L. Ghrelin cells replace insulin-producing beta cells in two mouse models of pancreas development. Proc Natl Acad Sci USA. 2004;101:2924-2929. [PubMed] [DOI]|
|79.||Dezaki K, Hosoda H, Kakei M, Hashiguchi S, Watanabe M, Kangawa K, Yada T. Endogenous ghrelin in pancreatic islets restricts insulin release by attenuating Ca2+ signaling in beta-cells: implication in the glycemic control in rodents. Diabetes. 2004;53:3142-3151. [PubMed] [DOI]|
|80.||Wierup N, Svensson H, Mulder H, Sundler F. The ghrelin cell: a novel developmentally regulated islet cell in the human pancreas. Regul Pept. 2002;107:63-69. [PubMed] [DOI]|
|81.||Irako T, Akamizu T, Hosoda H, Iwakura H, Ariyasu H, Tojo K, Tajima N, Kangawa K. Ghrelin prevents development of diabetes at adult age in streptozotocin-treated newborn rats. Diabetologia. 2006;49:1264-1273. [PubMed] [DOI]|
|82.||Granata R, Settanni F, Biancone L, Trovato L, Nano R, Bertuzzi F, Destefanis S, Annunziata M, Martinetti M, Catapano F. Acylated and unacylated ghrelin promote proliferation and inhibit apoptosis of pancreatic beta-cells and human islets: involvement of 3’,5’-cyclic adenosine monophosphate/protein kinase A, extracellular signal-regulated kinase 1/2, and phosphatidyl inositol 3-Kinase/Akt signaling. Endocrinology. 2007;148:512-529. [PubMed] [DOI]|
|83.||Adeghate E, Ponery AS. Ghrelin stimulates insulin secretion from the pancreas of normal and diabetic rats. J Neuroendocrinol. 2002;14:555-560. [PubMed] [DOI]|
|84.||Sun Y, Asnicar M, Smith RG. Central and peripheral roles of ghrelin on glucose homeostasis. Neuroendocrinology. 2007;86:215-228. [PubMed] [DOI]|
|85.||Lee HM, Wang G, Englander EW, Kojima M, Greeley GH. Ghrelin, a new gastrointestinal endocrine peptide that stimulates insulin secretion: enteric distribution, ontogeny, influence of endocrine, and dietary manipulations. Endocrinology. 2002;143:185-190. [PubMed] [DOI]|
|86.||Dezaki K, Sone H, Koizumi M, Nakata M, Kakei M, Nagai H, Hosoda H, Kangawa K, Yada T. Blockade of pancreatic islet-derived ghrelin enhances insulin secretion to prevent high-fat diet-induced glucose intolerance. Diabetes. 2006;55:3486-3493. [PubMed] [DOI]|
|87.||Doi A, Shono T, Nishi M, Furuta H, Sasaki H, Nanjo K. IA-2beta, but not IA-2, is induced by ghrelin and inhibits glucose-stimulated insulin secretion. Proc Natl Acad Sci USA. 2006;103:885-890. [PubMed] [DOI]|
|88.||Colombo M, Gregersen S, Xiao J, Hermansen K. Effects of ghrelin and other neuropeptides (CART, MCH, orexin A and B, and GLP-1) on the release of insulin from isolated rat islets. Pancreas. 2003;27:161-166. [PubMed] [DOI]|
|89.||Wierup N, Yang S, McEvilly RJ, Mulder H, Sundler F. Ghrelin is expressed in a novel endocrine cell type in developing rat islets and inhibits insulin secretion from INS-1 (832/13) cells. J Histochem Cytochem. 2004;52:301-310. [PubMed] [DOI]|
|90.||Barnett BP, Hwang Y, Taylor MS, Kirchner H, Pfluger PT, Bernard V, Lin YY, Bowers EM, Mukherjee C, Song WJ. Glucose and weight control in mice with a designed ghrelin O-acyltransferase inhibitor. Science. 2010;330:1689-1692. [PubMed] [DOI]|
|91.||Lomonaco R, Ortiz-Lopez C, Orsak B, Webb A, Hardies J, Darland C, Finch J, Gastaldelli A, Harrison S, Tio F. Effect of adipose tissue insulin resistance on metabolic parameters and liver histology in obese patients with nonalcoholic fatty liver disease. Hepatology. 2012;55:1389-1397. [PubMed] [DOI]|
|92.||Arner P. Insulin resistance in type 2 diabetes: role of fatty acids. Diabetes Metab Res Rev. 2002;18 Suppl 2:S5-S9. [PubMed] [DOI]|
|93.||Miles JM, Nelson RH. Contribution of triglyceride-rich lipoproteins to plasma free fatty acids. Horm Metab Res. 2007;39:726-729. [PubMed] [DOI]|
|94.||Choi SS, Diehl AM. Hepatic triglyceride synthesis and nonalcoholic fatty liver disease. Curr Opin Lipidol. 2008;19:295-300. [PubMed] [DOI]|
|95.||Neuschwander-Tetri BA. Nontriglyceride hepatic lipotoxicity: the new paradigm for the pathogenesis of NASH. Curr Gastroenterol Rep. 2010;12:49-56. [PubMed] [DOI]|
|96.||Cusi K. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. Gastroenterology. 2012;142:711-725.e6. [PubMed] [DOI]|
|97.||Sozio MS, Liangpunsakul S, Crabb D. The role of lipid metabolism in the pathogenesis of alcoholic and nonalcoholic hepatic steatosis. Semin Liver Dis. 2010;30:378-390. [PubMed] [DOI]|
|98.||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. [PubMed] [DOI]|
|99.||Li Z, Xu G, Qin Y, Zhang C, Tang H, Yin Y, Xiang X, Li Y, Zhao J, Mulholland M. Ghrelin promotes hepatic lipogenesis by activation of mTOR-PPARγ signaling pathway. Proc Natl Acad Sci USA. 2014;111:13163-13168. [PubMed] [DOI]|
|100.||Ibrahim SH, Kohli R, Gores GJ. Mechanisms of lipotoxicity in NAFLD and clinical implications. J Pediatr Gastroenterol Nutr. 2011;53:131-140. [PubMed] [DOI]|
|101.||Musso G, Cassader M, De Michieli F, Rosina F, Orlandi F, Gambino R. Nonalcoholic steatohepatitis versus steatosis: adipose tissue insulin resistance and dysfunctional response to fat ingestion predict liver injury and altered glucose and lipoprotein metabolism. Hepatology. 2012;56:933-942. [PubMed] [DOI]|
|102.||Kern PA, Ranganathan S, Li C, Wood L, Ranganathan G. Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am J Physiol Endocrinol Metab. 2001;280:E745-E751. [PubMed]|
|103.||Grigorescu M, Crisan D, Radu C, Grigorescu MD, Sparchez Z, Serban A. A novel pathophysiological-based panel of biomarkers for the diagnosis of nonalcoholic steatohepatitis. J Physiol Pharmacol. 2012;63:347-353. [PubMed]|
|104.||Crespo J, Cayón A, Fernández-Gil P, Hernández-Guerra M, Mayorga M, Domínguez-Díez A, Fernández-Escalante JC, Pons-Romero F. Gene expression of tumor necrosis factor alpha and TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients. Hepatology. 2001;34:1158-1163. [PubMed] [DOI]|
|105.||Wren AM, Seal LJ, Cohen MA, Brynes AE, Frost GS, Murphy KG, Dhillo WS, Ghatei MA, Bloom SR. Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab. 2001;86:5992. [PubMed] [DOI]|
|106.||Kamegai J, Tamura H, Shimizu T, Ishii S, Sugihara H, Wakabayashi I. Chronic central infusion of ghrelin increases hypothalamic neuropeptide Y and Agouti-related protein mRNA levels and body weight in rats. Diabetes. 2001;50:2438-2443. [PubMed] [DOI]|
|107.||Nakazato M, Murakami N, Date Y, Kojima M, Matsuo H, Kangawa K, Matsukura S. A role for ghrelin in the central regulation of feeding. Nature. 2001;409:194-198. [PubMed] [DOI]|
|108.||Shintani M, Ogawa Y, Ebihara K, Aizawa-Abe M, Miyanaga F, Takaya K, Hayashi T, Inoue G, Hosoda K, Kojima M. Ghrelin, an endogenous growth hormone secretagogue, is a novel orexigenic peptide that antagonizes leptin action through the activation of hypothalamic neuropeptide Y/Y1 receptor pathway. Diabetes. 2001;50:227-232. [PubMed] [DOI]|
|109.||Arslan N, Sayin O, Tokgoz Y. Evaluation of serum xenin and ghrelin levels and their relationship with nonalcoholic fatty liver disease and insulin resistance in obese adolescents. J Endocrinol Invest. 2014;Epub ahead of print. [PubMed]|
|110.||Williams DL, Grill HJ, Cummings DE, Kaplan JM. Overfeeding-induced weight gain suppresses plasma ghrelin levels in rats. J Endocrinol Invest. 2006;29:863-868. [PubMed] [DOI]|
|111.||Palik E, Baranyi E, Melczer Z, Audikovszky M, Szöcs A, Winkler G, Cseh K. Elevated serum acylated (biologically active) ghrelin and resistin levels associate with pregnancy-induced weight gain and insulin resistance. Diabetes Res Clin Pract. 2007;76:351-357. [PubMed] [DOI]|
|112.||Hosojima H, Togo T, Odawara T, Hasegawa K, Miura S, Kato Y, Kanai A, Kase A, Uchikado H, Hirayasu Y. Early effects of olanzapine on serum levels of ghrelin, adiponectin and leptin in patients with schizophrenia. J Psychopharmacol. 2006;20:75-79. [PubMed] [DOI]|
|113.||Otukonyong EE, Dube MG, Torto R, Kalra PS, Kalra SP. High-fat diet-induced ultradian leptin and insulin hypersecretion are absent in obesity-resistant rats. Obes Res. 2005;13:991-999. [PubMed] [DOI]|
|114.||Perez-Tilve D, Heppner K, Kirchner H, Lockie SH, Woods SC, Smiley DL, Tschöp M, Pfluger P. Ghrelin-induced adiposity is independent of orexigenic effects. FASEB J. 2011;25:2814-2822. [PubMed] [DOI]|
|115.||Müller TD, Tschöp MH, Jarick I, Ehrlich S, Scherag S, Herpertz-Dahlmann B, Zipfel S, Herzog W, de Zwaan M, Burghardt R. Genetic variation of the ghrelin activator gene ghrelin O-acyltransferase (GOAT) is associated with anorexia nervosa. J Psychiatr Res. 2011;45:706-711. [PubMed] [DOI]|
|116.||Waseem T, Duxbury M, Ito H, Ashley SW, Robinson MK. Exogenous ghrelin modulates release of pro-inflammatory and anti-inflammatory cytokines in LPS-stimulated macrophages through distinct signaling pathways. Surgery. 2008;143:334-342. [PubMed] [DOI]|
|117.||Chorny A, Anderson P, Gonzalez-Rey E, Delgado M. Ghrelin protects against experimental sepsis by inhibiting high-mobility group box 1 release and by killing bacteria. J Immunol. 2008;180:8369-8377. [PubMed] [DOI]|
|118.||Wu R, Dong W, Ji Y, Zhou M, Marini CP, Ravikumar TS, Wang P. Orexigenic hormone ghrelin attenuates local and remote organ injury after intestinal ischemia-reperfusion. PLoS One. 2008;3:e2026. [PubMed] [DOI]|
|119.||Kasımay O, Işeri SO, Barlas A, Bangir D, Yeğen C, Arbak S, Yeğen BC. Ghrelin ameliorates pancreaticobiliary inflammation and associated remote organ injury in rats. Hepatol Res. 2006;36:11-19. [PubMed] [DOI]|
|120.||Huang CX, Yuan MJ, Huang H, Wu G, Liu Y, Yu SB, Li HT, Wang T. Ghrelin inhibits post-infarct myocardial remodeling and improves cardiac function through anti-inflammation effect. Peptides. 2009;30:2286-2291. [PubMed] [DOI]|
|121.||Gonzalez-Rey E, Chorny A, Delgado M. Therapeutic action of ghrelin in a mouse model of colitis. Gastroenterology. 2006;130:1707-1720. [PubMed] [DOI]|