Elusive liver factor that causes pancreatic α cell hyperplasia: A review of literature

Abstract

Tumors and cancers of the gastrointestinal tract and pancreas are commonly derived from precursor lesions so that understanding the physiological, cellular, and molecular mechanisms underlying the pathogenesis of precursor lesions is critical for the prevention and treatment of those neoplasms. Pancreatic neuroendocrine tumors (PNETs) can also be derived from precursor lesions. Pancreatic α cell hyperplasia (ACH), a specific and overwhelming increase in the number of α cells, is a precursor lesion leading to PNET pathogenesis. One of the 3 subtypes of ACH, reactive ACH is caused by glucagon signaling disruption and invariably evolves into PNETs. In this article, the existing work on the mechanisms underlying reactive ACH pathogenesis is reviewed. It is clear that the liver secretes a humoral factor regulating α cell numbers but the identity of the liver factor remains elusive. Potential approaches to identify the liver factor are discussed. lesions. One of the precursor lesions, reactive pancreatic α cell hyperplasia is caused by glucagon signaling disruption and invariably evolves into pancreatic neuroendocrine tumors. In this article, the existing work on the mechanisms underlying the novel precursor lesion is reviewed. It is clear that the liver secretes a humoral factor regulating pancreatic α cell numbers but the identity of the liver factor remains elusive. Potential approaches to identify the liver factor are discussed.Yu R, Zheng Y, Lucas MB, Tong YG. Elusive liver factor that causes pancreatic α cell hyperplasia: A review of literature. World J Gastrointest Pathophysiol 2015; 6(4): 131-139 Available from:

Interrupted Glucagon Signaling Reveals Hepatic α Cell Axis and Role for L-Glutamine in α Cell Proliferation

“…Interrupting GCGR signaling by various ways leads to α-cell proliferation, and a hepatic-derived circulating mitogen has been proposed (Longuet et al, 2013; Yu et al, 2015). Using a comprehensive multimodal approach and three models with altered glucagon signaling, we found the activity resides in <10kDa fraction of mouse serum, alterations in genes regulating hepatic AA catabolism, and increased serum AA levels.…”

Newly discovered endocrine functions of the liver

“…Although a physiological compensation of hyperglucagonemia in animals and humans with inactive GCGR is quite intuitive, the specific mechanism of the compensation was initially not clear[ 67 ]. The liver-specific GCGR knockout mice interestingly have similar α cell hyperplasia and hyperglucagonemia, as those in global GCGR knockout mice[ 57 , 58 , 68 ], suggesting that the liver is the only target organ of glucagon that sends feedback signals to α cells, and that loss of the usual negative feedback mechanism stimulates α cell hyperplasia and glucagon secretion.…”

“…The liver may regulate α cells via neural or humoral mechanisms[ 67 , 68 ]. Islet transplantation experiments demonstrate that the liver uses a humoral mechanism[ 68 ].…”

“…Initially, it was hoped that a single liver hormone would be isolated from differential liver gene expression patterns of wild-type and GCGR knockout mice[ 67 ]. Several groups, including ours, performed liver mRNA arrays of GCGR knockout mice and in wild-type mice treated with inhibitory GCGR antibodies, using wild-type mice as control[ 67 , 68 , 72 ].…”

“…Initially, it was hoped that a single liver hormone would be isolated from differential liver gene expression patterns of wild-type and GCGR knockout mice[ 67 ]. Several groups, including ours, performed liver mRNA arrays of GCGR knockout mice and in wild-type mice treated with inhibitory GCGR antibodies, using wild-type mice as control[ 67 , 68 , 72 ]. Not surprisingly, many genes are overexpressed (potential stimulatory hormones) or underexpressed (potential inhibitory hormones) in the GCGR knockout liver[ 67 , 68 , 72 ].…”