Increased SLC38A4 Amino Acid Transporter Expression in Human Pancreatic α-Cells After Glucagon Receptor Inhibition

Kim, Jinrang; Gutiérrez, Giselle Domínguez; Xin, Yurong; Cavino, Katie; Sung, Biin; Sipos, Bence; Kloeppel, Guenter; Gromada, Jesper; Okamoto, Haruka

doi:10.1210/en.2019-00022

Cited by 20 publications

(14 citation statements)

References 18 publications

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“…In contrast, we observed low signal intensity for SLC38A4, SLC7A2, and SLC7A8 with no specific cellular localization or specificity to tumor cells. In agreement with recent work, 22 we observed modest SLC38A4 transcript upregulation Report ll OPEN ACCESS (3.1-fold tumor 1, 1.6-fold tumor 2); however, we observed no consequential protein expression in tumor cell membranes or lysosomes (Figure S2A). Having demonstrated that mouse SLC38A5-expressing tumor cells are the dominant proliferative population, we next co-immunostained SLC7A8 and MKI67 in each human specimen to evaluate whether SLC7A8-expressing tumor cells are proliferative.…”

Section: Expression Analysis Of Human Loss-of-function Gcgr Tumors Identifies Slc7a8 and Lack Of Immune Infiltrationsupporting

confidence: 93%

“…[14][15][16][17][18][19][20][21] Ultimately, chronic disruption of GCGR signaling results in gross PNET formation in aged mice and humans. [22][23][24][25][26][27] Taking advantage of this defined genetic model, we systematically characterized PNET progression using genetically engineered Gcgr knockout mice and identified a proliferative SLC38A5 + cell of origin in mTOR-dependent, immune-restricted adenomas harboring low mutational burden. Importantly, alpha cells of young and aged adult wild-type mice retain transcriptional plasticity and adopt a similar proliferative SLC38A5 + progenitor-like identity in response to elevated plasma amino acids.…”

Section: Introductionmentioning

confidence: 99%

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Elevated Serum Amino Acids Induce a Subpopulation of Alpha Cells to Initiate Pancreatic Neuroendocrine Tumor Formation

Kates¹,

Durinck²,

Patel³

et al. 2020

Cell Reports Medicine

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Summary The cellular origin of sporadic pancreatic neuroendocrine tumors (PNETs) is obscure. Hormone expression suggests that these tumors arise from glucagon-producing alpha cells or insulin-producing β cells, but instability in hormone expression prevents linage determination. We utilize loss of hepatic glucagon receptor (GCGR) signaling to drive alpha cell hyperproliferation and tumor formation to identify a cell of origin and dissect mechanisms that drive progression. Using a combination of genetically engineered Gcgr knockout mice and GCGR-inhibiting antibodies, we show that elevated plasma amino acids drive the appearance of a proliferative population of SLC38A5 + embryonic progenitor-like alpha cells in mice. Further, we characterize tumors from patients with rare bi-allelic germline GCGR loss-of-function variants and find prominent tumor-cell-associated expression of the SLC38A5 paralog SLC7A8 as well as markers of active mTOR signaling. Thus, progenitor cells arise from adult alpha cells in response to metabolic signals and, when inductive signals are chronically present, drive tumor initiation.

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Section: Expression Analysis Of Human Loss-of-function Gcgr Tumors Identifies Slc7a8 and Lack Of Immune Infiltrationsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Elevated Serum Amino Acids Induce a Subpopulation of Alpha Cells to Initiate Pancreatic Neuroendocrine Tumor Formation

Kates¹,

Durinck²,

Patel³

et al. 2020

Cell Reports Medicine

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“…These findings did, however, not translate into human islets implanted into mice despite an observed alpha cell proliferation following pharmacological glucagon receptor inhibition [121]. Rather, glucagon receptor inhibition in mice with implanted human islets elicited an increased pancreatic expression of the amino acid transporter Slc38a4 [151]. When investigating molecular mechanisms responsible for increasing alpha cell mass in both rodents and implanted human islets after glucagon receptor blockade, the mechanistic target of the rapamycin (mTOR) pathway has been suggested to be involved [121,151].…”

Section: Glucagon Receptor Signalingmentioning

confidence: 99%

“…Rather, glucagon receptor inhibition in mice with implanted human islets elicited an increased pancreatic expression of the amino acid transporter Slc38a4 [151]. When investigating molecular mechanisms responsible for increasing alpha cell mass in both rodents and implanted human islets after glucagon receptor blockade, the mechanistic target of the rapamycin (mTOR) pathway has been suggested to be involved [121,151]. However, this is a relatively broad signaling cascade involved in multiple cellular functions including mitosis, and therefore it is of interest to search for potential, more specific downstream targets of amino acid induced alpha cell proliferation.…”

Section: Glucagon Receptor Signalingmentioning

confidence: 99%

Glucagon Receptor Signaling and Glucagon Resistance

Janah

Kjeldsen

Galsgaard

et al. 2019

IJMS

122

102

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Hundred years after the discovery of glucagon, its biology remains enigmatic. Accurate measurement of glucagon has been essential for uncovering its pathological hypersecretion that underlies various metabolic diseases including not only diabetes and liver diseases but also cancers (glucagonomas). The suggested key role of glucagon in the development of diabetes has been termed the bihormonal hypothesis. However, studying tissue-specific knockout of the glucagon receptor has revealed that the physiological role of glucagon may extend beyond blood-glucose regulation. Decades ago, animal and human studies reported an important role of glucagon in amino acid metabolism through ureagenesis. Using modern technologies such as metabolomic profiling, knowledge about the effects of glucagon on amino acid metabolism has been expanded and the mechanisms involved further delineated. Glucagon receptor antagonists have indirectly put focus on glucagon’s potential role in lipid metabolism, as individuals treated with these antagonists showed dyslipidemia and increased hepatic fat. One emerging field in glucagon biology now seems to include the concept of hepatic glucagon resistance. Here, we discuss the roles of glucagon in glucose homeostasis, amino acid metabolism, and lipid metabolism and present speculations on the molecular pathways causing and associating with postulated hepatic glucagon resistance.

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“…These data suggest that other transporters may play a role in both mouse and human a-cell proliferation. Recently, Okamoto and colleagues searched for common features in the expression of amino acid transporter genes in human islets transplanted into Gcgr antibody-treated mice (29). They found that the neutral amino acid transport SLC38A4, the cationic amino acid transporter SLC7A2, and the Q-dependent amino acid exchanger SLC7A8 with its heavy-chain SLC3A2 Figure 2-A liver-a-cell axis that reciprocally regulates amino acid homeostasis and a-cell function and proliferation.…”

mentioning

confidence: 99%

A Primary Role for α-Cells as Amino Acid Sensors

Dean

2019

Diabetes

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Glucagon and its partner insulin are dually linked in both their secretion from islet cells and their action in the liver. Glucagon signaling increases hepatic glucose output, and hyperglucagonemia is partly responsible for the hyperglycemia in diabetes, making glucagon an attractive target for therapeutic intervention. Interrupting glucagon signaling lowers blood glucose but also results in hyperglucagonemia and α-cell hyperplasia. Investigation of the mechanism for α-cell proliferation led to the description of a conserved liver–α-cell axis where glucagon is a critical regulator of amino acid homeostasis. In return, amino acids regulate α-cell function and proliferation. New evidence suggests that dysfunction of the axis in humans may result in the hyperglucagonemia observed in diabetes. This discussion outlines important but often overlooked roles for glucagon that extend beyond glycemia and supports a new role for α-cells as amino acid sensors.

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Increased SLC38A4 Amino Acid Transporter Expression in Human Pancreatic α-Cells After Glucagon Receptor Inhibition

Cited by 20 publications

References 18 publications

Elevated Serum Amino Acids Induce a Subpopulation of Alpha Cells to Initiate Pancreatic Neuroendocrine Tumor Formation

Elevated Serum Amino Acids Induce a Subpopulation of Alpha Cells to Initiate Pancreatic Neuroendocrine Tumor Formation

Glucagon Receptor Signaling and Glucagon Resistance

A Primary Role for α-Cells as Amino Acid Sensors

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