Reply to “Letter to Editor: Chronic alcohol exposure alters circulating insulin and ghrelin levels in hepatic steatosis: a translational research perspective”

reply: We appreciate the constructive comments and suggestions by Pandey (23) in her Letter to the Editor regarding our recent manuscript on the role of ghrelin in the development of alcoholic steatosis (24). We are pleased that the author felt our manuscript (24) presented novel insights into the effects of ghrelin in modulating the pancreas-adipose-liver axes and promoting the development of alcoholic steatosis. We value the author’s suggestion that further investigations into the potential involvement of ghrelin receptor-mediated calcium ion channel regulation in the development of steatosis should be conducted, which could provide novel insights into the complex signal transduction pathways of ghrelin action. The specific receptor for ghrelin, growth hormone secretagogue receptor (GHS-R), is widely expressed in many peripheral tissues and in various regions of the brain and exists in two isoforms, GHS-R1a and GHS-R1b (9, 12, 32). GHS-R1a, the widely studied form, is functionally active but is a promiscuous target for ghrelin as it displays heterogenous signaling cascades based on the tissue type. To illustrate this point, in the pituitary, ghrelin induces somatotrophin release by triggering intracellular calcium release (19). However, ghrelin binding to GHSR-1a on pancreatic β cells leads to an inhibition of intracellular calcium levels, which disrupts insulin secretion (5). Interestingly, both alcoholic and nonalcoholic fatty liver injury have been shown to be associated with impaired Ca²⁺ signaling, which dysregulates glucose and lipid metabolism and alters bile secretion, mitochondrial function, and survival of hepatocytes (2, 20, 26). Thus, examining the role of ghrelin in modulating Ca²⁺-dependent pathways in hepatocytes and adipocytes would indeed provide a novel understanding of the pathogenic role of ghrelin in liver diseases of various etiologies.

The second fascinating avenue as indicated by Pandey (23) is to study receptor heterogenicity and receptor cointeractions. GHS-R1a, the active receptor highly expressed in many organs, is a 7 transmembrane-spanning G protein-coupled receptor, whereas GHS-R1b, which lacks domains 6 and 7 of the type1a, is thought to represent a nonfunctional receptor (9, 21). The 5 transmembrane GHS-R1b receptor also exhibits widespread tissue distribution. This isoform colocalizes with GHS-R1a and is recognized as attenuating its signal transduction capacity (4). Indeed, it has been suggested that, at least in neurons, GHS-R1b may determine the ability of GHS-R1a to form oligomeric complexes with other receptors (22). On this latter aspect, GHS-R1a receptor can in fact cointeract with several additional G protein-coupled receptors such as melanocortin 3 receptor, dopamine receptors (D1 and D2), and serotonin 2C receptor. Such cointeractions lead to either attenuation or augmentation of GHS-R1a-mediated signaling (3, 11, 14, 16). Whether such heterodimerizations also exist in the organs and tissues of interest to us, such as adipose and liver, certainly warrants further investigation. Note that our study is one of a handful of publications illustrating the direct effect of ghrelin on the liver. This field is in its infancy and hopefully we can soon offer mechanistic insights into cross-talk with other receptors.

There are many laboratories worldwide that are presently examining the genetic basis of alcoholic liver disease (ALD). Currently identified SNPs [Patatin-like phospholipase domain containing 3 (PNPLA3) transmembrane 6 superfamily 2 (TM6SF2), membrane-bound O-acyltransferase domain-containing 7 gene (MBOAT7), and hydroxy-steroid 17-β dehydrogenase 13 (HSD17B13)] are all involved in lipid metabolism/processing, perhaps supporting inflammation and fibrogenesis during ALD progression (18). These SNPs have also been reported in nonalcoholic fatty liver disease (NAFLD) (18). It will be interesting to examine the association of the identified GHS-R (6, 27, 28) and ghrelin (13, 29) polymorphisms with the severity and prognosis of these diseases, which could aid in the identification of “at-risk” susceptible individuals.

Based on our published studies (24), it portends that modulating ghrelin and or its receptor could be a favorable therapeutic option for treating alcoholic fatty liver disease. Current studies are underway in our laboratory to test the ability of GHS-R1a blockers in preventing and/or treating alcoholic steatosis. We are currently also feeding alcohol to GHS-R KO rats (30, 31) (kindly provided by Professor Lorenzo Leggio, National Institute on Alcohol Abuse and Alcoholism /National Institute on Drug Abuse, NIH) to further elucidate the pathogenic role of ghrelin in alcoholic hepatic steatosis. Finally, while our work and Dr. Pandey’s reply focus on the ghrelin receptor, future work may also be warranted on how other components that influence the ghrelin system may interplay in developing alcoholic steatosis, e.g., the ghrelin O-acyl transferase enzyme that acylates ghrelin, which is required for binding and activating its receptor (8, 15, 17), the recently discovered ghrelin antagonist, liver-expressed antimicrobial peptide-2 (LEAP-2) (1, 7) and the role of cannabinoid receptor type 1 (CBR1) in the formation of active ghrelin (10, 25).

GRANTS

This paper is supported by National Institute on Alcohol Abuse and Alcoholism Grant K01 AA024254-01A1.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

K.R., C.A.C., and K.K.K. drafted manuscript; K.R., C.A.C., and K.K.K. edited and revised manuscript; K.R., C.A.C., and K.K.K. approved final version of manuscript.