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Regulation ofProtein Synthesis 77

Downloaded from https://onlinelibrary.wiley.com/doi/ by Universität Bern, Wiley Online Library on [22/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

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CCK

eIF4E–Kinase

4E-BP1

eIF4E

4E-BP1

eIF4E

m7GTP

Formation of eIF4F complex

Figure8.1 CCK and insulin stimulate translational initiation

through the P13K- PKB- mTORC1 pathway. mTORC1, which can be inhibited by rapamycin, phosphorylates the eIF4E- binding protein

BP1) that allows the release of eIF4E and the formation of the

(4EeIF4F complex necessary for a global increase in translation. mTORC1 also phosphorylates S6K1, which is responsible for phosphorylating S6, thereby increasing the translation of a specific subset of mRNAs. CCK also increases the activity of an eIF4EK, leading to phosphorylation of eIF4E. Together, these effects lead to an increase in protein synthesis Adapted from[28].

eIF4A

eIF4G

and initiation of

global translation

Insulin

PI3-K

Wortmannin

Akt/PKB

Rapamycin

mTORC1

S6K

mRNA

S6 Ribosomal protein

Increased

translation

at the translation initiation level in mice after 2 h of feeding [38]. When protein or the amino acid leucine are removed from the diet, postprandial pancreatic digestive enzyme synthesis is strongly inhibited, and their deficiency could induce pancreatic insufficiency and malnutrition. The inhibition of protein synthesis and decreased polysomal fraction, caused by the reduction of protein, or only leucine in the diet, has a similar general effect, but it is induced by different mechanisms: protein deficiency causes a partial reduction of the activation of mTORC1 and the guanine nucleotide exchange factor eIF2B; whereas leucine deficiency causes an amino acid imbalance that activates the general controlled nonrepressed (GCN2) kinase, that, in turn, increases eIF2α phosphorylation that blocks protein synthesis[38].

Other studies have shown how dietary protein and amino acids stimulate pancreatic protein synthesis and pancreatic growth in rats[39] and mice[8] fed for several days. Branched- chain amino acids (BCAA), particularly leucine, also stimulate the phosphorylation of 4EBP1 and S6K and the formation of the eIF4F complex in mice and rats, without the need for an increase in the hormones CCK and insulin[40]. A mechanism has been described for a direct stimulation of protein synthesis by amino acids

through mTORC1 [35,40–42], and it seems that amino acids are necessary both as a signal and as a substrate for pancreatic digestive enzyme synthesis after a meal[38].

The effects of food can also be mediated by GI and systemic hormones and neurotransmitters. Their stimulatory mechanisms have been mainly studied in isolated pancreatic acini [43]. CCK, carbachol, insulin, and bombesin all stimulate the synthesis of total protein, trypsinogen, chymotrypsinogen, lipase, and amylase in isolated rat acini[44–46]. These invitro studies demonstrate that CCK and insulin, at their stimulatory doses, have an additive effect on protein synthesis after 30 min, and that this effect is mainly at the translational level because it occurs without a change in mRNA levels and in the presence of actinomycin D[46,47]. Increased synthesis of both digestive enzymes and structural proteins was observed, although differences between individual proteins suggested nonparallel translational effects[47].

CCK stimulates protein synthesis in isolated rat acini and in the whole animal[48–50], by increasing the rate of translation initiation[48–51] and elongation[52], at concentrations that stimulate digestive enzyme secretion. Additionally, CCK or its analogue caerulein, activates the S6k inase (S6K)[53,54] and the phosphorylation of eIF4E[50,51] and activates the formation of the eIF4F complex by stimulating the release of eIF4E from its binding protein 4E- BP1 and increasing the association of eIF4E with eIF4G[35,51]. These actions are summarized in Fig.8.1. The activation of S6K, the formation of the eIF4F complex, and the activation of the elongation processes and eEF2 appear to be regulated through a rapamycin- sensitive pathway and to be downstream of phosphatidylinositol 3- kinase (PI3K) [49,52,53]. The calcium–calmodulin- activated phosphatase calcineurin is also involved in the activation of CCK- stimulated pancreatic protein synthesis and the regulation of the translational machinery [50]. As mentioned earlier, insulin also stimulates protein synthesis in pancreatic acini invitro [45] by activating the eIF4F complex formation, in a similar manner to CCK[49]. Insulin stimulates pancreatic digestive enzyme synthesis invivo, after a meal. This has been demonstrated with the use of pancreatic acinar cell conditional insulin receptor (IR) knockout mice[54]. The activation of the Akt/mTORC1 pathway is reduced in the pancreas of these mice after 2 h of a meal feeding, and also the translational machinery and polysomal fraction. Additionally, the protein content of the stimulated pancreatic juice is reduced, but not the total pancreatic juice volume, compared with their littermate controls. This demonstrates that insulin is an important physiologic regulator of the pancreatic digestive enzyme synthesis and acinar cell homeostasis that could lead to pancreatic insufficiency during diabetes[28].

Regulation ofPancreatic Protein Synthesis andGrowth

Supraphysiological CCK concentrations

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At concentrations of CCK and cholinergic analogues that inhibit secretion[43], protein synthesis is also inhibited[44,48,55]. In minced rabbit pancreas, however, only a decrease in protein synthesis was observed in response to CCK, and this was accompanied by a decrease in the number of polysomes[55].

Inhibition of Pancreatic Protein Synthesis. Endoplasmic Reticulum (ER) Stress and Unfolded Protein Response (UPR)

Invivo, inhibition of pancreatic protein synthesis occurs during the development of acute pancreatitis[56]. This inhibition is accompanied by a reduction in the activity of the guanine nucleotide exchange factor eIF2B, an increase in eIF2α phosphorylation, and a decrease in the formation of the eIF4F complex [48,50,56] (Fig. 8.2). Additionally, this inhibitory effect appears to be calcium related, because the incubation of isolated acini in calcium- free media or with A23187 and thapsigargin to release intracellular Ca2+ increases eIF2α phosphorylation and inhibits eIF2B activity. This suggests that pancreatic acinar cells adapt to short- term stress induced by reduction in calcium stores by inhibiting protein synthesis of pancreatic enzymes[48,55]. The ER- resident kinase (PERK)[57] mediates eIF2α phosphorylation in the exocrine pancreas[58,59] and activates the ER stress mechanisms. The inhibition of protein synthesis associated with high concentrations of CCK could therefore be an

Thapsigargin

release: Depletion of Ca

A23187

eIF2B

Inhibition of the attachment

of met-tRNA to ribosomes

Figure8.2 Mechanism by which high concentrations of CCK and

induction of ER stress inhibit initiation of translation. Depletion of intracellular Ca kinase (such as PERK), which phosphorylates eIF2α and thereby inhibits eIF2B. This inhibition results in a decrease in protein synthesis Adapted from[28].

eIF2-GDP

(–)

eIF2-GTP

stores or other forms of ER stress activates a

ER stress

PERK

eIF2α-P

stores

adaptive or protective mechanism in response to stress localized in the ER[48,56].

ER stress mechanisms are protective cellular responses to stress in the ER, due to an accumulation of unfolded or misfolded proteins in this cellular compartment that trigger the UPR [59]. ER stress and UPR mechanisms have been described in some experimental models of acute pancreatitis[56,60], in pancreatic acinar cell damage in vitro [61], and in induced pancreatic acinar cell damage due to alcohol abuse invivo[62].

Regulation ofPancreatic Growth

The pancreas arises embryologically as an outgrowth of the foregut that develops through a relatively undifferentiated ductunder the influence of mesenchyme and a number of transcriptional regulators[63]. By birth, the pancreas has assumed its fully differentiated form and histology but continues thereafter to grow in parallel with body growth. Depending on the species, this can occur by hypertrophy or hyperplasia. A recent study showed that rodent pancreas grows predominantly by hypertrophy, and human pancreas by hyperplasia [64]. During this period, growth of the acinar cell mass is by selfduplication of acinar cells[65]. While all acinar cells can divide, some studies have shown a subset that divides faster in normal growth and regeneration [66]. In the adult animal, acinar and islet cells were originally assumed to be no longer dividing but in fact they both show a small but finite turnover that can be accelerated by hormones and diet. Hence the acinar and beta islet cells are considered to exist in the Go phase of the cell cycle rather than being terminally differentiated. Whether undifferentiated stem cells remain in the adult pancreas or if small duct cells can function as stem cells remains controversial.

In the exocrine pancreas, enhanced growth in response to hormones or diet can take the form of cellular hypertrophy in which protein increases in excess of DNA resulting in larger cells, or cellular hyperplasia marked by an increase in DNA resulting in more cells. Normally in hyperplasia, protein increases in parallel with DNA, so the endpoint is normal- sized cells. In hypertrophy and hyperplasia, there is usually an increased total digestive enzyme content in the pancreas, although the concentration relative to DNA or total protein may or may not change. Although not as well studied, glandular atrophy can result from loss of cellular protein, as seen with protein- deficient diets[17], or from loss of cells, as seen with some forms of pancreatitis following apoptosis or necrosis. Two distinct types of in vivo growth to be discussed are adaptive growth in response to diet and

like state into acini, islets, and mature ducts

Regulation ofPancreatic Growth 79

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hormones and regeneration following the loss of functional cells. The use of cell culture as a model for pancreatic growth will also be reviewed.

Adaptive Growth inResponse toNutrients andHormones

To ensure adequate nutrient absorption, the amount and composition of digestive enzymes secreted by the pancreas must complement the size and macronutrient composition of a meal. Although the synthesis and secretion of digestive enzymes can increase with consumption of larger and/or more frequent meals, this capacity is finite. Another mechanism whereby the pancreas can adapt to increased feeding is through growth of the acinar cells. Both a high- protein diet and hyperphagia that occurs with cold exposure, pregnancy, and lactation are associated with pancreatic growth[1].

GI hormones released after a meal may contribute to the growth- promoting effects of feeding on the exocrine pancreas as CCK, secretin, and gastrin have all been shown to induce pancreatic growth[67]. The effects of CCK have been studied extensively in rodents and have been reviewed previously[43,68]. Direct administration of CCK or caerulein induces acinar cell growth invivo[1,67,69], and invitro[70]. Feeding a high- protein diet and especially synthetic or naturally occurring trypsin inhibitors, such as those found in raw soy flour, prevents feedback regulation of CCK secretion and culminates in maintained high concentrations of circulating CCK[71], which also stimulates pancreatic growth[72]. Oral trypsin inhibitor- induced pancreatic growth is blocked by coadministration of CCK antagonists [73] and is absent in CCK[74] and CCK- A receptor- deficient mice[75]. In the rat, CCK- stimulated growth is primarily through cellular hypertrophy, but with some hyperplasia, whereas in mice it is primarily through hyperplasia. In both cases, the hyperplasia involves DNA synthesis and replication of mature acinar cells [76]. Although CCK can mediate adaptive growth, it does not appear to be essential for growth during development and CCK or its receptors are not necessary in most studies for maintenance of normal pancreatic size. In contrast to CCK, the hormone secretin had little effect by itself but can potentiate the action of CCK[67].

More recently, information has emerged on intracellular pathways mediating pancreatic growth (Fig.8.3). CCK is known to activate a number of intracellular pathways potentially related to growth, including an increase in intracellular Ca

, three MAPK pathways, and the PI3KmTOR pathway [43]. Most of these pathways are activated in the pancreas in response to endogenous CCK release following feeding of camostat[77]. Pharmacologic and genetic evidence exists for three major intracellular

pathways, calcineurin–NFAT, mTORC1, and ERK1/2, playing nonredundant roles in adaptive pancreatic growth. The calcineurin–NFAT pathway can be blocked pharmacologically with the calcineurin inhibitors FK506 and cyclosporin A and genetically by overexpression of Rcan1[74,78,79]. The mTORC1 pathway can be blocked with rapamycin[80] or by acinar cell- specific deletion of Raptor, an essential component of mTORC1 (SJ Crozier, MD Sans, and JA Williams, unpublished data). The ERK pathway can be blocked with specific MEK inhibitors active invivo such as PD- 0325901[81]. Blockage of each of these pathways blocks pancreatic adaptive growth induced by feeding camostat. These pathways are important regulators of mRNA transcription and translation, and it is likely through modulation of these processes that CCK affects pancreatic growth by activating the cell cycle.

Polyamines have also been studied as mediators of pancreatic growth induced by CCK and other hormones[82]. The naturally occurring polyamines putrescine, spermidine, and spermine are normal cell components involved in protein and DNA synthesis. Biosynthesis of polyamines is initiated by ornithine decarboxylase and its inhibitor difluoromethylornithine inhibits pancreatic growth in response to CCK. However, there is no clear role for polyamines in pancreatic growth and it may be that they are simply a cellular component necessary for pancreatic growth similar to their role in intestinal adaptation and liver regeneration.

Growth of the pancreas in response to CCK administration is greatly diminished in rats fed a low- protein diet[83]. Conversely, consumption of large amounts of protein induces pancreatic hypertrophy in rodents[84], even in the presence of a CCK receptor antagonist[18] and in CCK- deficient mice[85]. Therefore, it appears that dietary protein both potentiates the effects of CCK on pancreatic growth and also stimulates pancreatic growth via CCK- independent mechanisms. These CCKindependent mechanisms are undoubtedly mediated, at least in part, by amino acids. Purified amino acids do not stimulate CCK secretion, yet ingestion of large quantities of amino acids stimulates pancreatic growth [18]. This action is mediated in large part by the mTORC1 pathway, which is activated by amino acids [8]. Interestingly, growth of the pancreas in mice fed a high- protein diet occurs predominately via cellular hypertrophy [85] whereas that associated with supraphysiologic levels of CCK, such as direct CCK administration and trypsin inhibitor feeding, in mice is primarily hyperplastic[74]. It may be that a threshold level of CCK exists, above which signal transduction pathways are activated that permit cell division following cellular hypertrophy.

Other systemic hormones, including insulin[20], thyroid hormones, and glucocorticoids, can stimulate and regulate pancreatic growth in response to meal feeding[1,86].

Regulation ofPancreatic Protein Synthesis andGrowth

CCK

ession

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Amino Acids

mTORC1

eIF4E

4E-BP1

S6K1

eIF4E

Figure8.3 Intracellular pathways through

which CCK stimulates pancreatic growth. At least three pathways involving calcineurin-

MEK

Calcineurin

NFATs

ERK1/2

ERK1/2have been shown to be necessary for growth of rodent pancreas either invivo or invitro. Inhibitors of all three pathways can block growth Adapted from[1].

NFAT, mTORC1, and

Translational

Control of

Protein Synthesis

Pancreatic Growth

(Mitogenesis and Hypertrophy

Activation of vagal nerve fibers to the pancreas during feeding stimulates the release of additional peptides associated with secretion of bicarbonate and digestive enzymes. Some of these neuropeptides may also play a role in the regulation of pancreatic growth and their effects have been reviewed previously[87]. In particular, vasoactive intestinal polypeptide (VIP) potentiates the effects of caerulein on pancreatic growth in a manner similar to secretin and gastrin- releasing peptide and bombesin stimulate pancreatic growth, although not as strongly as CCK.

Regeneration

Despite the low rate of cellular turnover normally observed in the adult pancreas, studies in rodents have demonstrated its ability to regenerate in response to tissue injury[88]. This has been studied both after pancreatitis and following surgical resection. Experimental pancreatitis induced by caerulein, arginine, bile salts, or ethionine leads to cell death by a combination of apoptosis and necrosis. The remaining acinar cells dedifferentiate and form tubular complexes that express both acinar and ductal characteristics and some markers of embryonic pancreas. These cells divide and grow and eventually differentiate back into mature acinar cells [89–91]. At present, there is little definitive evidence for regeneration from stem cells.

Following surgical resection of 50–90% of the rat pancreas, the remnant pancreas increases in size and protein and DNA content, with the increase being greater after more complete resection [92]. However, the pancreas never regains its normal size and islets appear to regenerate to a greater extent than exocrine tissue. In some

Transcriptional

Control of

Gene expr

reports differentiated acinar cells are said to incorporate thymidine or show mitotic figures, whereas in other studies regeneration is reported to occur in the injured margin and show tubular complexes and express embryonic markers[93]. In mice, a 75% resection was followed by growth of the remnant by 40%, with evidence for proliferation of differentiated acinar cells[94].

Similarly, to adaptive growth, dietary protein, CCK, and insulin play a significant role in the regeneration of exocrine cells following pancreatic injury. The pancreas is incapable of regeneration in rats fed a protein- free diet. Both exogenous and endogenous CCK enhance and CCK receptor antagonists slow the rate of pancreatic regeneration following pancreatitis[95]. There is also a significant decrease in the rate of pancreatic regeneration in mice lacking the CCK- A receptor in the pancreas[96]. The importance of insulin is shown by the fact that in diabetic rats, CCK administration fails to induce pancreatic regeneration following pancreatitis unless exogenous insulin is also administered[97]. Pertinently, it has been demonstrated that the expression of IGF- 1 mRNA is significantly increased following pancreatitis and resection, indicating that both insulin and IGF may be important in pancreatic regeneration.

The expression of cellular oncogenes that regulate the cell cycle and thereby control cellular proliferation rates is significantly increased in models of pancreatic regeneration[98,99]. Many genes associated with embryonic development, and whose expression is normally repressed in the adult, are re- expressed during pancreatic regeneration following pancreatitis[90]. Only a little is known of signal transduction pathways that mediate these changes in gene expression. The p42/p44MAPK pathway, which modulates the expression of cell- cycle

References 81

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regulators, is activated in the regenerating pancreas [100]. Activation of the PI3K pathway has been shown to be necessary for pancreatic regeneration following resection, as inhibition of the pathway via pharmacologic inhibitors or siRNA severely diminished regeneration [94]. Moreover, the PI3K pathway activation in response to resection decreased with age and may contribute to the reduced regenerative capacity of the aged pancreas. Further identification of the signal transduction pathways, and also the factors modulating these pathways, will be important for improving our understanding of pancreatic regeneration.

Growth ofPancreatic Cells inCulture

In vitro culture of differentiated or immortalized cells can be used as models for cell growth. Most pancreatic cancer cell lines, however, are undifferentiated and will not be considered here. Primary dissociated pancreatic cells, although not dividing, can be maintained in suspension culture under conditions such that they retain the differentiated phenotype or where they dedifferentiate and adopt a more plastic phenotype. When isolated acinar cells or acini are placed on an extracellular matrix such as collagen or matrigel, the cells will initiate division and remain viable for several weeks but almost invariably lose their differentiated appearance. CCK or its analogue caerulein can stimulate cell division and growth, as do insulin, epithermal growth factor (EGF), and other growth factors[70,101]. This model has been applied to evaluating which intracellular pathways mediate growth, with evidence for participation by Ras [102], PI3K/ Akt[94], and MAPK pathways[103]. The

dedifferentiated

phenotype of cultured acinar cells was originally reported as duct like [104,105]. Subsequently, they were characterized as similar to precursor cells that can transdifferentiate into insulin-

containing islet cells [106] and that the dedifferentiated cells can simultaneously express acinar, ductal, or beta- cell proteins. Another report showed retention of acinar cell phenotype with an altered medium containing a high amino acid level [107]. In a similar manner, pancreatic duct cells have been grown in monolayer culture. They retain their ion- transporting phenotype and have been used to study duct function. Their growth in culture is stimulated by EGF, TGFα, and insulin, inhibited by TGFβ, but not affected by secretin or other GI peptides[108].

Although no real differentiated pancreatic acinar cell line exists, considerable research has been carried out with AR42J cells, a rat cell line derived from an azoserineinduced tumor which under the influence of glucocorticoids assumes a more acinar phenotype[109]. However, these cells were subsequently shown also to have neuroendocrine properties and can even be driven toward an islet phenotype such that they appear more like an undifferentiated ductal epithelium. Their growth can be stimulated by CCK, gastrin, PACAP, and other peptides, but only to 25–30% and not after exposure to dexamethasone, which induces acinar differentiation but inhibits growth[109].

In summary, all the cultured pancreatic cells studied to date, although dividing and regulated by hormones, possess a relatively undifferentiated phenotype. Hence, they are more a model for regenerating pancreas after pancreatitis than they are a model for diet- or hormonedriven acinar proliferation.

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Fibrogenesis inthe Pancreas: The Role ofPancreatic Stellate Cells

Minoti V. Apte

Pancreatic Research Group, South Western Sydney Clinical Campus, School of Clinical Medicine, UNSW Medicine and Health, University of New South

Wales, Sydney, NSW, Australia

Ingham Institute for Applied Medical Research, Liverpool, NSW, Australia

1, 2

, Romano C. Pirola

1, 2

, and Jeremy S. Wilson

1, 2

Introduction

Fibrogenesis is defined as the development or production of fibrous tissue. In the healthy pancreas, fibrogenesis is a well- controlled, regulated process that is essential for regular turnover of extracellular matrix (ECM) in the parenchyma, thereby maintaining normal pancreatic architecture. In diseased states, however, this process is hijacked such that the fine balance between production and degradation of fibrous tissue is disrupted, leading to the deposition of excessive amounts of ECM proteins in the organ, eventually resulting in pathologic fibrosis.

Elucidation of the cellular and molecular mechanisms involved in pancreatic fibrogenesis began in earnest in 1998, when methods were developed to isolate and culture pancreatic stellate cells (PSC), now established as key cells in the fibrogenic process, from rodent and human pancreas [1–3]. Interestingly, the presence of these cells in the pancreas was first reported by Watari etal.[4] in Japan a decade and a half earlier (in 1982), and confirmed by Ikejiri [5] in 1990. However, little was known of their function at the time. It was the subsequent development of techniques to isolate viable PSC from the pancreas that provided the much-

needed invitro tool that enabled researchers to interrogate the functions of these cells both in health and in pancreatic disease.

Pancreatic Stellate Cells (PSC)

PSC inHealth

PSC comprise 4–7% of total parenchymal cells in the normal pancreas. They are found around the basolateral

aspects of acinar cells (Fig.9.1a), blood vessels, and small pancreatic ducts[1,2] and also around pancreatic islets[6].

In their native, quiescent (non- activated) state, PSC store abundant vitamin A (retinoids) in their cytoplasm and belong to a larger “stellate cell system” in the body, comprising retinoid storing cells in several other organs, including the liver, lungs, intestine, kidney, spleen, and adrenal glands[7]. The specific density imparted by the stored lipid enabled Apte etal.[1] to develop the density gradient centrifugation method for the isolation of quiescent PSC from the pancreas. This method has since been refined and further customized by several groups to suit their experimental purposes. The presence of cytoplasmic vitamin A droplets (Fig. 9.1b), and the expression of selective markers such as the intermediate filaments desmin, glial fibrillary acidic protein (GFAP) and nestin, and the neuroectodermal proteins neural cell adhesion molecule and nerve growth factor differentiate PSC from fibroblasts. Due to the expression of neural markers, PSC were initially thought to be of neuroectodermal origin. However, lineage tracing studies with hepatic stellate cells (counterparts of PSC in the liver) have confirmed a mesenchymal origin for these cells[8]. The fact that a proportion of PSC are replenished from bone marrow further supports a mesenchymal origin for PSC[9].

Islet stellate cells (ISC) are similar to but differ in certain aspects from PSC. ISC have fewer vitamin A- containing droplets and undergo a more rapid activation than PSC. Upon activation, ISC express more α- SMA but have reduced rates of proliferation and migration compared with exocrine PSC[6].

Initial studies were focused on the ability of PSC to maintain normal extracellular matrix turnover in health, by not only synthesizing ECM proteins such as collagen,

The Pancreas: An Integrated Textbook of Basic Science, Medicine, and Surgery, Fourth Edition. Edited by Hans G. Beger, Markus W. Büchler, RalphH. Hruban, Julia Mayerle, John P. Neoptolemos, Tooru Shimosegawa, Andrew L. Warshaw, David C. Whitcomb, and Yupei Zhao. © 2023 John Wiley & Sons Ltd. Published 2023 by John Wiley & Sons Ltd. Companion website: www.wiley.com/go/beger/thepancreas4e

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