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Heliyon 10 (2024) e31296
Available online 22 May 2024
2405-8440/© 2024 Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license
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Review article
Long-chain fatty acids - The turning point between ‘mild’ and
‘severe’ acute pancreatitis
Qiang Liu
a
,
c
,
d
, Xinyi Gu
b
, Xiaodie Liu
b
, Ye Gu
a
, Hongchen Zhang
a
,
Jianfeng Yang
a
,
b
,
c
,
d
,
**
, Zhicheng Huang
a
,
b
,
*
a
Department of Gastroenterology, Afliated Hangzhou First People’s Hospital, Westlake University School of Medicine, Hangzhou 310058, China
b
The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou 310003, China
c
Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou
310058, China
d
Hangzhou Hospital & Institute of Digestive Diseases, Hangzhou, Zhejiang 310006, China
ARTICLE INFO
Keywords:
Acute pancreatitis
Long-chain fatty acids
Acinar cells
Macrophages
Lipase
Inammatory responses
ABSTRACT
Acute pancreatitis (AP) is an inammatory disease characterized by localized pancreatic injury
and a systemic inammatory response. Fatty acids (FAs), produced during the breakdown of
triglycerides (TGs) in blood and peripancreatic fat, escalate local pancreatic inammation to a
systemic level by damaging pancreatic acinar cells (PACs) and triggering M1 macrophage po-
larization. This paper provides a comprehensive analysis of lipases’ roles in the onset and pro-
gression of AP, as well as the effects of long-chain fatty acids (LCFAs) on the function of
pancreatic acinar cells (PACs). Abnormalities in the function of PACs include Ca
2+
overload,
premature trypsinogen activation, protein kinase C (PKC) expression, endoplasmic reticulum (ER)
stress, and mitochondrial and autophagic dysfunction. The study highlights the contribution of
long-chain saturated fatty acids (LC-SFAs), especially palmitic acid (PA), to M1 macrophage
polarization through the activation of the NLRP3 inammasome and the NF-κB pathway.
Furthermore, we investigated lipid lowering therapy for AP. This review establishes a theoretical
foundation for pro-inammatory mechanisms associated with FAs in AP and facilitating drug
development.
1. Introduction
Acute pancreatitis (AP) is an inammatory disease with an increasing incidence rate. It has been reported that 34 individuals per
10,000 suffer from AP worldwide [1]. AP is caused by factors such as pancreatic duct obstruction, alcohol abuse, and hyperlipidemia. It
triggers local or systemic inammatory responses resulting from pancreatic acinar cell (PAC) death [2]. Mild acute pancreatitis
frequently subdues on its own and resolves in 1–2 weeks. Moderately severe pancreatitis or severe acute pancreatitis can cause local
complications and systemic organ failure with long periods of hospitalization and/or permanent organ dysfunction. Diffusion of the
* Corresponding author. Afliated Hangzhou First People’s Hospital, Westlake University School of Medicine, Hangzhou 310058, China.
** Corresponding author. Department of Gastroenterology, Afliated Hangzhou First People’s Hospital, Westlake University School of Medicine,
Hangzhou, China.
E-mail addresses: liuqiang0825@zju.edu.cn (Q. Liu), 531481899@qq.com (X. Gu), lxd291142632@163.com (X. Liu), chinesegu@foxmail.com
(Y. Gu), hongchen_zhang@126.com (H. Zhang), yangjf3303@sina.com (J. Yang), 1301443043@qq.com (Z. Huang).
Contents lists available at ScienceDirect
Heliyon
journal homepage: www.cell.com/heliyon
https://doi.org/10.1016/j.heliyon.2024.e31296
Received 15 August 2023; Received in revised form 14 May 2024; Accepted 14 May 2024
Heliyon 10 (2024) e31296
2
local inammatory response is thought to be critical for in exacerbating AP progression. As such, identifying the factors that increase
inammation is imperative for the development of effective therapeutic drugs. There is ample evidence to suggest that the progression
of hypertriglyceridemia-induced acute pancreatitis (HTG-AP) is more severe than that of AP caused by any other etiology [3].
Obesity-related physiological indicators, including body mass index, large abdominal circumference, elevated visceral fat levels
and hyperlipidemia, are signicantly linked to the incidence and severity of AP [4]. Catabolism of triglycerides (TGs) around the
pancreas and in the bloodstream is believed to play a crucial role in the development of AP [5]. The initial stage of AP involves injury to
the pancreatic acinar cells (PACs), triggering the release of pancreatic lipase into the peripancreatic region and bloodstream. Lipase
release leads to TGs breakdown in both the bloodstream and peripancreatic fat. TGs are catabolized into fatty acids (FAs) and glycerol
by lipase-induced hydrolysis. FAs modulate cell functions and can be divided into two categories based on the presence or absence of
double bonds: saturated fatty acids (SFAs) and unsaturated fatty acids (UFAs). FAs can be classied based on the length of their carbon
chains into short-chain fatty acids, medium-chain fatty acids and long-chain fatty acids (LCFAs). LCFAs are the main components of
animal fats, participating in the functional regulation of cells and inammatory responses. Palmitic acid (PA) is considered to be the
primary long-chain saturated fatty acid (LC-SFA) that causes chronic inammation in obese patients. Oleic acid (OA) and linoleic acid
(LA), which are long-chain unsaturated fatty acid(LC-UFA), can mitigate the detrimental effects of PA [6]. PA hinder organelle
functions, including those of mitochondria, autophagosomes, lysosomes, and the endoplasmic reticulum (ER), in PACs. As a result,
PACs become more vulnerable to invasion in the AP. Moreover, PA can activate the NF-κB signaling pathway in macrophages and
promote the inammatory response involving the NLRP3 inammasome [7]. Although LC-UFAs are widely recognized for their
anti-inammatory effects, high concentrations of LC-UFAs induce the necrosis of PACs, which increases the release of cell contents via
cell membrane rupture. This, in turn, contributes to an amplied inammatory response and hastens the development of AP [5,8,9].
Furthermore, fatty acid metabolites, such as fatty acid chlorohydrin and fatty acid ethyl esters (FAEEs) are involved in damaging PACs
[10,11]. This paper provides a comprehensive analysis of lipase in AP, specically examining the effects of PA and OA on Ca
2+
overload, premature trypsinogen activation, protein kinase C (PKC) expression, ER stress, mitochondrial dysfunction, and autophagic
dysfunction in PACs. Furthermore, this study outlines the diverse mechanisms through which PA induces M1 macrophage polarization
by stimulating the NLRP3 inammasome and the NF-κB pathway. Furthermore, we investigated lipid lowering therapy for AP. The
potential of FA isoforms for predicting and treating AP is also briey discussed.
2. Lipase catabolism in TGs mediates the onset and progression of AP
During AP, pancreatic enzymes leak from the injured PACs to the periphery of the pancreas, where they catalyze the catabolism of
TGs. The storage and secretion of digestive enzymes in PACs are polarized and directional processes: digestive enzymes are released
from the apical membrane into the lumen without touching the basement membrane side where fat is located [12]. However, in AP,
this process is disrupted, and pancreatic enzymes in PACs pass through the basement membrane through exocytosis and leak into the
periphery of the pancreas, where they contact peripancreatic fat [12–14]. Lipases, including pancreatic triacylglycerol lipase (PNLIP),
pancreatic lipase-related protein 2, and carboxyl ester lipase (CEL), are the primary pancreatic digestive enzymes associated with
peripancreatic lipolysis. PNLIP is critical for breaking down dietary fats, as well as peripancreatic fat [15]. Nevertheless, the partic-
ipation of CEL in peripancreatic lipolysis depends on high concentrations of bile salts (>200 mmol/L), which are unavailable in AP
[16]. In addition, CEL can break down only short six-carbon acyl chains [17] and is incapable of decomposing long-chain peri-
pancreatic fat molecules [5,18]. Although CEL cannot mediate peripancreatic lipolysis, it mediates alcoholic AP by catalyzing the
synthesis of FAEEs. The CEL inhibitor 3-benzyl-6-chloro-2-pyrone (3-BCP) alleviates FAEE-induced cytotoxicity [19]. Long-term
alcohol consumption increases the content of fatty acid synthase in PACs [20], which catalyzes the synthesis of FAEEs from
ethanol and intracellular FAs through a nonoxidizing pathway [21], resulting in the destruction of PACs and the onset of alcoholic AP.
Although pancreatic lipase-related protein 2 hydrolyzes TGs in the absence of bile salts [16], it is rarely secreted and has a restricted
function in lipolysis [22]. In addition to pancreatic lipase, adipose tissue also contains lipases, such as adipose triglyceride lipase
(ATGL) and hormone-sensitive lipase (HSL) [23]. ATGL is the initial and rate-limiting lipase [24], and HSL is coregulated by glucagon,
growth hormone, thyroid hormone, and epinephrine, which are involved in the hydrolysis of fat and the elevation of blood glucose
levels. Although ATGL can be decomposed by trypsin during AP [15], ethanol can stimulate ATGL activity in obese mice to decompose
peripancreatic fat and generate FAs, ultimately causing pancreatic injury [25]. ATGL is responsible for inducing alcoholic pancreatitis
in obese individuals through lipolysis in the peripancreatic fat.
In addition to the breakdown of TGs derived from peripancreatic fat, lipase possesses the capacity to hydrolyze blood TGs. The
process of lipase-induced TGs hydrolysis within the pancreatic vascular bed leads to the formation of FAs, a mechanism hypothesized
to be one of the pathogenic pathways in HTG-AP [26]. Moreover, once AP is initiated, the release of lipase from PACs into the cir-
culation could potentially trigger the breakdown of blood TGs and systemic lipolysis, thereby contributing to the overall systemic
inammatory response.
Lipases exert diverse functions in the onset and progression of AP. The breakdown of the TGs by PNLIP leading to AP exacerbation is
a known phenomenon. CEL catalyzes the synthesis of palmitoleic acid and ethanol into FAEEs which in turn impairs PACs inducing
alcoholic pancreatitis. Alcohol stimulates ATGL in the peripancreatic fat to participate in TGs catabolism, producing FAs that damage
the PACs and induce obesity-alcoholic pancreatitis. These ndings imply that abnormalities in the expression and functionality of
lipase within pancreatic and adipose tissues, particularly in conditions such as obesity and alcohol dependence, may predispose in-
dividuals. Furthermore, HSL is a potential lipase implicated in systemic lipolysis, contributing to the development of AP under hor-
monal disruptions. The identication of lipase activity is crucial for assessing population susceptibility and formulating lipase-targeted
therapies for AP treatment. Advancements in lipase activity assay technology provide a robust foundation for ongoing research in this
Q. Liu et al.
Heliyon 10 (2024) e31296
3
domain [27].
3. LCFAs cause acinar cell damage and death by inducing cellular events
Abnormal accumulation of LCFAs occurs through fat decomposition, which leads to destruction of the pancreas and its surrounding
tissues. The utilization of the lipase inhibitor orlistat mitigated pancreatic damage in an AP mouse model [28,29]. LC-UFAs and
LC-SFAs, produced via lipolysis, synergistically regulate cellular activity and inammatory responses. For example, High concen-
trations of PA were cytotoxic to PACs. Conversely, OA alleviated lipid toxicity [30,31]. However, the impact of OA on PACs, whether
protective or detrimental, is concentration-dependent [8,9,32].
3.1. Typical manifestations of pancreatitis induced by LC-UFAs–mitochondrial dysfunction and Ca
2+
overload
High concentrations of LC-UFAs can cause mitochondrial dysfunction, which is a crucial step in damaging PACs. Beyond OA,
various other LC-UFAs, including LA and docosahexaenoic acid (DHA), have the potential to induce Ca
2+
overload in PACs at high
concentration (Fig. 1a), resulting in ongoing opening of the mitochondrial permeability transition pore (MPTP) (Fig. 1b). This causes
cytoplasmic components to enter the mitochondrial matrix, resulting in mitochondrial swelling and loss of membrane potential [33,
34]. Furthermore, Ca
2+
overload can induce mitochondrial dysfunction, subsequently leading to a surge in reactive oxygen species
(ROS) production and a decrease in ATP synthesis. This ultimately results in premature trypsinogen activation. Upon its release,
trypsin triggers autodigestion within and beyond PACs, including the mitochondria. Additionally, elevated levels of LA can impede the
activation of mitochondrial complexes I and V [32]. The decrease in ATP production effectively disrupts the function of sarcoplasmic
endoplasmic reticulum calcium-ATPases (SERCAs) and plasma membrane calcium ATPases (PMCAs), which are pivotal for removing
Ca
2+
from the cytoplasma, leading to Ca
2+
overload [35]. Galactose supplementation has been demonstrated to mitigate this Ca
2+
overload by supplying additional ATP to cells [36]. Research indicates that ROS can also induce persistent MPTP channel opening [34].
The activation of the MPTP channel is contingent upon cyclophilin D (CypD). Therefore, either CypD knockout or the application of a
targeted small-molecule inhibitor (TRO40303) can offer protection against mitochondrial depolarization [37,38]. The mitigation of
Ca
2+
overload can be achieved through the inhibition of Ca
2+
inux and release, as well as an increase in Ca
2+
efux. Melatonin has
been shown to reduce pancreatic damage by upregulating SERCAs expression, thereby alleviating Ca
2+
overload [39]. Research has
indicated that dantrolene-mediated inhibition of ryanodine receptors (RyRs) effectively diminishes Ca
2+
release from the ER in the
granule region [40]. Furthermore, exposing PACs to caffeine inhibits 1,4,5-trisphosphate receptor (IP3R)-mediated Ca
2+
oscillations
[41]. Importantly, LC-UFAs do not appear to trigger Ca
2+
release via the IP3R and RyRs pathways [8]. The potential mechanisms for
Ca
2+
overload induced by high concentrations of LC-UFAs could involve the inhibition of SERCAs and PMCAs functions, leading to a
reduction in Ca
2+
efux. These ndings warrant further investigation.
Fig. 1. Effect of high concentrations of OA on acinar cell function. (a) High concentrations of OA cause a continuous increase in Ca
2+
levels,
resulting in Ca
2+
overload. (b) Continuous opening of the MPTP induced by high intracellular concentrations of Ca
2+
causes mitochondrial
dysfunction, decreased ATP production and disordered prothrombin secretion. (c) CN regulates premature trypsinogen activation. (d) OA regulates
premature trypsinogen activation by upregulating PKC expression. (e) Cathepsin B released from lysosomes induces cell necroptosis and pyroptosis
by stimulating RIP1-RIP3 and NLRP3.
Q. Liu et al.
Heliyon 10 (2024) e31296
4
3.2. LC-UFAs mediate impaired autophagy, premature trypsinogen activation, and death in PACs
Autophagy is a collective term for several pathways through which cytoplasmic materials are delivered to the lysosome and
degraded by lysosomal hydrolases. This process involves organelles such as autophagosomes, lysosomes, and autolysosomes. Impaired
autophagy leads to the premature trypsinogen activation associated with AP. The impairment of autophagy caused by mitochondrial
dysfunction may involve damage to lysosomes through ROS generated by dysfunctional mitochondria or impaired delivery of hy-
drolases to lysosomes due to a decrease in ATP [42]. Furthermore, trypsinogen activation is regulated by both PKC and calcineurin
(CN). High concentrations of LC-UFAs upregulate the expression of PKC, while Ca
2+
overload induced by high concentrations of
LC-UFAs mediates trypsinogen activation through CN [8,43–46] (Fig. 1c and d). During AP, there is a concomitant breakdown of
polyamines, a natural anti-inammatory substance. The reduction of polyamines activates cathepsin B, which in turn leads to the
premature trypsinogen activation. Supplementing with the polyamine analog N(1), N(11)-diethylnorspermine and bismethylspermine
can prevent the premature trypsinogen activation [47,48].
Sarah et al. have reported that increased levels of LC-UFAs can instigate cell necrosis [32], a phenomenon potentially attributable to
the release of cathepsin B, which is triggered by damaged lysosomes. Furthermore, cathepsin B can cause necroptosis of PACs through
the receptor-interacting protein kinase 1 (RIP1)–RIP3 pathway [49] (Fig. 1e). The inhibition of this RIP1–RIP3 pathway, either
through genetic modulation or the use of necrostatin (an inhibitor of RIP1), can mitigate the severity of PACs injury. Consequently, this
presents a potential therapeutic target for AP therapy [50]. The study of NLRP3 inammasome-mediated cell death is a signicant area
of current research. The identication of the NLRP3 inammasome in PACs provides a fresh perspective for investigating the role of
LC-UFAs in acinar cell death, given that cathepsin B can activate the NLRP3 inammasome, thereby triggering pyroptosis [51].
Furthermore, cathepsin B induces conformational alterations in the proapoptotic proteins Bax and Bid, which are situated within
mitochondria and create pores on the mitochondrial membrane [52], which activates caspase-3/9 and ultimately triggers apoptosis.
Although there are multiple modes of cell death, the preferred mode may be inuenced by factors such as the concentration of
LC-UFAs, the degree of trypsinogen activation, and cathepsin B leakage [50,52]. Given that different modes of death can exhibit
varying degrees of proinammatory effects, it is crucial to investigate the specic mode of cell death induced by LC-UFAs. Research has
shown that the promotion of apoptosis can effectively mitigate inammation in AP [53,54]. It is postulated that inhibiting pyroptosis
and necroptosis in PACs could facilitate better control of inammation in AP. The application of mimic peptides to inhibit NLRP3
inammasome-mediated acinar cell pyroptosis may provide targeted therapies for AP [55]. Furthermore, Celastrol and baicalin have
been found to inhibit necroptosis by reducing the activity of the RIPK1–RIPK3 pathway in mice with AP [56,57].
3.3. LC-UFAs participate in the development of AP through PKC expression
PKC plays a vital role in regulating multiple functions within the healthy pancreas and is involved in AP. PKC isoforms are
associated with amylase secretion, trypsinogen activation, and NF-κB activation. Four subtypes of PKC, namely, PKC
α
, PKCδ, PKC
ε
,
and atypical PKCζ have been identied in PACs [8]. For instance, PKC
α
releases trypsin from the basolateral membrane, allowing it to
enter peripancreatic tissue. Conversely, trypsin is not released from the apical membrane, which leads to entry into the pancreatic duct
[58]. PKCδ and PKC
ε
are involved in the activation of trypsinogen and the transcription factor NF-κB [46,59]. Once activated, PKCδ is
translocated to the plasma membrane and participates in amylase secretion [60]. In AP, the expression of PKC
α
, PKCδ, and PKC
ε
is
upregulated under the stimulation of various LC-UFAs, whereas the expression of PKCζ is primarily inuenced by DHA and arachidonic
acid [8].
Low levels of LC-UFAs have a protective impact on PACs in AP mouse model. However, high amounts of LC-UFAs can induce AP-
specic symptoms such as Ca
2+
overload, premature trypsinogen activation, and expression of PKC. The mitigation of Ca
2+
overload is
vital for preserving the internal homeostasis of PACs. Previously, the exact pathways through which LC-UFAs instigate Ca
2+
overload
remained elusive. The inhibition of SERCAs and PMCAs functions present potential pathways that warrant further investigation.
Currently, research into various types of cell death is a topic of signicant interest. Premature trypsinogen activation leads to an
increase in lysosomal membrane fragility and the release of Cathepsin B. This latter can trigger necroptosis and pyroptosis via the
activation of both the RIP1-RIP3 pathway and the NLRP3 inammasome. The identication of the NLRP3 inammasome within the
PACs implies that LC-UFAs may induce pyroptosis in this specic region. Furthermore, Sarah et al. have reported that high concen-
trations of LC-UFAs can provoke necrosis within the PACs [32]. Investigating the mechanisms behind PAC death is vital for managing
the spread of inammation. To mitigate the inammatory response in AP, it is necessary to limit the occurrence of pyroptosis, nec-
roptosis, and necrosis while simultaneously promoting apoptosis.
3.4. LC-SFAs induce PAC dysfunction by impairing autophagy
Impaired autophagy has been noted in the PACs of HTG-AP animal models, with LC-SFAs playing a pivotal role in this process [61].
The regulation of autophagy is largely dependent on key proteins such as mammalian target of rapamycin (mTOR) and AMP-activated
protein kinase (AMPK) [62,63]. High concentrations of PA activate mTOR, thereby inhibiting the fusion of autophagosomes and ly-
sosomes, which results in a decrease in autophagic ux. Mei et al. found that mice subjected to the HTG-AP model treated with the
mTOR inhibitor rapamycin demonstrated a signicant increase in autophagic ux [61]. Thioredoxin-interacting protein (TXNIP)
expression escalates in response to stimulation of PA, inhibiting mTOR and fostering FA oxidation, and improving autophagy [64,65].
However, the over-upregulation of TXNIP induced by high concentrations of PA can lead to impaired autophagy and inammatory
responses [66]. Consequently, targeting TXNIP could offer a potential therapeutic avenue for the treatment of HTG-AP [67]. AMPK
Q. Liu et al.
Heliyon 10 (2024) e31296
5
mitigates mTOR activity via phosphorylation, thereby promoting autophagy [68]. Beyond regulating mTOR, AMPK plays a role in lipid
metabolism. Activated AMPK augments the oxidation of FAs, thus inhibiting the accumulation of PA [69]. However, the expression of
AMP-activated protein kinase precursor (p-AMPK
α
) was notably diminished in an obese mouse model of AP. The AMPK agonist, 5-ami-
noimidazole-4-formamide ribonucleotide (AICAR), activates AMPK to decrease lipolysis and alleviate necroptosis, thereby amelio-
rating AP [70]. Furthermore, research indicates that spermidine can both inhibit mTOR and activate AMPK, playing a role in activating
autophagy and alleviating ER stress [71].
Alterations in the structure of the lysosomal membrane inuence its functionality. A reduction in cholesterol content within this
membrane impedes the fusion process between autophagosomes and lysosomes. PA diminished the cholesterol content within lyso-
somes by facilitating the transfer of cell membrane lipids to these organelles [72,73]. Furthermore, PA induced aberrant translocation
of Bax from the ER to lysosomes. This process augments lysosomal permeability and compromises its functional integrity [74,75]
(Fig. 2a).
ER stress and mitochondrial dysfunction signicantly contribute to impaired autophagy. One such factor is the presence of ROS,
which further exacerbates autophagy damage [76] (Fig. 2b). Moreover, a reduction in the ATP supply for the H
+
pump on the lysosome
membrane results in an internal environment that becomes increasingly alkaline. This alkalinization impedes the hydrolysis of internal
proteases [77]. The accumulation of PA metabolites, including diacylglycerols (DAGs), saturated phospholipids, and ceramides, within
the ER induces stress, thereby escalating the damage to autophagy [78,79] (Fig. 2c). Treatment with 4-phenylbutyrate sodium (4-PBA)
in an obese mouse model of AP has been shown to reduce ER stress and restore autophagy [61]. Trehalose, known for its ability to
enhance the efciency of autophagy, has been found to mitigate pancreatic injury and decrease the severity of AP in animal models.
Consequently, trehalose shows potential as a therapeutic agent for treating AP [80]. However, the exact mechanism by which trehalose
stimulates autophagy remains a subject of ongoing research [81].
3.5. LC-SFAs activate ER stress, leading to acinar cell dysfunction and inammation in AP
Toxins such as ethanol cause ER stress by increasing the demand for protein synthesis and decreasing ER-processing ability [82].
Autophagy and the unfolded protein response relieve ER stress, but exceeding the ER stress threshold can trigger cellular inammatory
pathways. Precise regulation of ER stress is therefore essential for cellular homeostasis [83]. High concentrations of PA exacerbate
CER-induced ER stress in PACs [30]. However, the molecular mechanism underlying PA-induced ER stress has largely not been
elucidated. Sarnyai and colleagues speculated that metabolites of PA may alter membrane protein biological functions by affecting the
morphology and uidity of the ER membrane [84]. Intracellular metabolites of PA, DAGs, saturated phospholipids and ceramides,
accumulate in the ER and are associated with structural damage [78,79]. Activation of the ER stress sensors IRE1
α
and PERK initiates a
cascade of events that culminate in the manifestation of ER stress [85,86]. Furthermore, PA inhibits diacylglycerol acyltransferase 2
activity by stimulating ROS production, which is the essential enzyme in the synthesis of TGs, leading to diglycerol accumulation in
PACs [87,88]. Low concentrations of OA promote the expression of diacylglycerol acyltransferase 2 (DGAT2) and carnitine
Fig. 2. Effect of SFAs on acinar cell function. (a) PA causes autophagy damage through lysosomal permeability, membrane composition and
alkalization. (b) PA increases the production of mitochondrial ROS by inhibiting mitochondrial complexes I and III, which directly damages
autophagy. (c) ER stress and autophagy injury can exacerbate each other.
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Heliyon 10 (2024) e31296
6
palmitoyltransferase I (CPT1), which aids in the oxidation of FAs and the synthesis of TGs, thereby reducing production of intermediate
products such as DAGs [87,89,90]. The polyphenolic antioxidant Urolithin A can restore the balance of mitochondrial fatty acid
oxidation metabolism and reduce the production of intermediate products [91]. In contrast, PA induced the excessive release of ROS
from mitochondria and autophagy dysfunction, which affects the ER function. Thus, PA aggravated PACs damage by triggering ER
stress and disrupting autophagy. Mei et al. have demonstrated that the activation of AMPK can alleviate the autophagy disruption and
ER stress induced by PA [61].
Ca
2+
overload is a manifestation of compromised mitochondrial function. One mechanism through which SFAs impede mito-
chondrial function is by inhibiting complexes I and III [76]. PA had the capacity to induce mitochondrial dysfunction, ER stress, and
autophagy damage, all of which contribute to abnormal PAC function. The adverse effects of PA on PACs appear to be amplied by
AP-inducing factors. For instance, upon treatment with PA, PACs exhibited a transient surge in intracellular Ca
2+
concentrations.
However, co-administration of PA and caerulein led to a prolonged elevation in these levels [92]. The detrimental impact of PA on
PACs appears to be exacerbated by AP causative factors. This may elucidate the heightened susceptibility and severity of AP observed
in obese patients.
4. LCFAs regulate the differentiation of macrophages
Consuming a high-fat diet leads to obesity. LC-SFAs generated by the decomposition of stored saturated fat stimulate the polari-
zation of M1 macrophages, contributing to chronic inammation in obese individuals. Appropriate proportions of LC-UFAs in fat
maintains a balanced proportions of M1 and M2 macrophages. In AP, necrotic adipose tissue leads to massive inltration of M1
macrophages, amplifying inammation and exacerbating organ injury in patients [93]. The product of lipolysis, LC-SFAs, are
considered as a key factor mediating this process. PA stimulates macrophages transformation into an inammatory phenotype and
induces the secretion of proinammatory factors and the suppression of anti-inammatory factors in AP [94–96].
4.1. PA activates NF-κB signaling to mediate M1 macrophage polarization
The activation of the NF-κB signaling pathway is a pivotal mechanism that mediates M1 macrophage polarization. This process
subsequently leads to the production of proinammatory factors, including IL-1β, TNF-
α
, and IL-6 [97–100]. The Toll-like receptor
(TLR) family is a crucial component in the activation of the NF-κB pathway. PA induces cellular oxidative stress and inammatory
responses by activating the TLR/NF-κB axis [101–103]. Hence, targeting TLR is considered a potential approach for mitigating the
intensity of the inammatory response in AP patients [102,104]. In addition, PA activates GPR40 receptors to induce an inammatory
response in macrophages [101], a proinammatory mechanism that requires further investigation (Fig. 3a). Moreover, ER stress and
Fig. 3. PA mediates M1 macrophage polarization by activating the NF-κB signaling pathway. (a) PA stimulates the Toll and FFA1 receptors to
stimulate a series of signaling pathways and ultimately activate NF-κB signaling. (b) Metabolites of PA cause ER stress, thus activating the NF-κB
signaling pathway. (c) UFAs activate PPARγ and inhibit the NF-κB signaling pathway. ER stress causes increased expression of FABP4, which
competitively binds to UFAs, resulting in PPARγ remaining inactive and unable to inhibit the NF-κB signaling pathway. (d) Autophagy injury
activates the NF-κB signaling pathway.
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Heliyon 10 (2024) e31296
7
lysosomal dysfunction are involved in the activation of the NF-κB pathway. On the one hand, the PA metabolites DAGs and ceramide
accumulate in the ER, causing structural damage and activating IRE1
α
and PERK, which then stimulate cytokine production via the
NF-κB pathway [85,86] (Fig. 3b). On the other hand, ER stress upregulates the expression of fatty-acid binding protein 4 (FABP4) [105,
106], which competes with peroxisome proliferator-activated receptor (PPARγ) to bind UFAs, restricting the specic activation of
PPARγ and disturbing mitochondrial function [7] (Fig. 3c). Moreover, FABP4 reduces the expression of sirtuin 3 (SIRT3) and
uncoupling protein 2 (UCP2) [107], which in turn results in increased generation of ROS. Consequently, elevated levels of ROS are
involved in the activation of NF-κB pathways. The polyphenolic antioxidant resveratrol can increase the expression of SIRT3, reduce
the generation of ROS, and thereby inhibit the activation of NF-κB pathways [108]. Promotion of PPARγ activity signicantly inhibits
the activation of the NF-κB pathway [109]. Furthermore, PA induces lysosome dysfunction-related autophagy, eventually resulting in
abnormal activation of the NF-κB pathway (Fig. 3d). PA induces and enhances NF-κB pathway activation through many mechanisms.
Interference with these pathways in AP is difcult because changes in one pathway are compensated by other proinammatory
pathways. The most effective way to attenuate the inammatory response to AP is to decrease the concentration of PA in blood and
peripancreatic tissues, as well as to design related receptor (TLR, FFA) agonists. Furthermore, inhibiting the migration of macrophages
to reduce their contact with activators is a feasible approach to suppress inammation. The polyphenolic antioxidant chlorogenic acid
reduced the serum and pancreatic levels of macrophage migration inhibitory factor in AP model [110].
4.2. PA activates the NLRP3 inammasome to mediate M1 macrophage polarization
The NLRP3 inammasome plays a crucial role in the macrophage response to microbial infections and cellular damage. Activation
of the NLRP3 inammasome occurs through two independent and parallel steps: priming and activation. The initial step entails
boosting the mRNA and protein levels of NLRP3 and pro-IL1β by activating NF-κB [111]. After priming, activation of the NLRP3
inammasome necessitates a second signal leading to oligomerization, caspase-1 activation, and the processing and release of IL1β and
IL18 [112]. Caspase-1 plays a pivotal role in modifying inammatory precursors and promoting the gasdermin-D induced pore for-
mation within the cell membrane. The activation signal comprises lysosomal dysfunction, K
+
efux, and mitochondrial dysfunction in
AP. PA plays a role in priming and activating the NLRP3 inammasome in macrophages [7,113]. The activation of NF-κB by PA has
been previously detailed and will not be reiterated herein. This paragraph focuses on PA activation of the NLRP3 inammatory
inammasome mediating M1 macrophage polarization (Fig. 4a).
Lysosomal dysfunction results in the secretion of cathepsin B to activate the NLRP3 inammasome [114]. PA and its metabolites are
responsible for inducing lysosomal dysfunction in macrophages. PA penetrates macrophages through the cluster of differentiation 36
(CD36) to form fatty acid crystals and eventually lead to lysosomal dysfunction [115] (Fig. 4b). Furthermore, PA metabolites, DAGs,
Fig. 4. PAs mediates M1 macrophage polarization by activating the NLRP3 inammasome. (a) ER stress increases the expression of FABP4, which
inhibits mitochondrial function, increases ROS production and hinders ATP production. (b) Phagocytized PA form crystals that damage lysosomes,
which release cathepsin B to activate the NLRP3 inammasome. (c) mtROS activate the NLRP3 inammasome. (d) ER stress increases the expression
of CD36 receptors. (e) mtROS stimulate TXNIP-TRX dissociation, and SFAs promote the expression of TXNIP. TXNIP stimulates the NLRP3
inammasome. (f) PA caused Na
+
-K
+
-ATP dysfunction by affecting membrane components, and decreased K
+
inux activated the NLRP3
inammasome.
Q. Liu et al.
Heliyon 10 (2024) e31296
8
saturated phospholipids and ceramides, activate ER stress, which in turn induces lysosomal dysfunction. First, ER stress triggers the
transfer of Bax to lysosomes, resulting in lysosomal membrane instability. Second, ER stress can upregulate CD36 expression [116],
which participates in PA transport and indirectly activates the NLRP3 inammasome. Moreover, ER stress activates the NLRP3
inammasome by increasing the overexpression of the TXNIP protein and directly or indirectly trigger increases in mitochondrial ROS
levels [117,118]. Furthermore, PA modulates the expression of AMPK and components of the mTOR signaling pathway, thereby
inhibiting autophagy. Additionally, PA diminishes the intracellular metabolism of FAs by impeding the activity of long-chain acyl-CoA
synthetase, leading to an accumulation of PA within the cell [119,120]. Physiological concentrations of LC-UFAs can mitigate the
activation of the NLRP3 inammasome and pyroptosis by reducing ER stress, thereby mitigating the effects of PA [121].
Mitochondrial dysfunction and associated mitochondrial reactive oxygen species (mtROS) generation are correlated with the
activation of the NLRP3 inammasome [122]. The induction of mitochondrial dysfunction is among the mechanisms by which PAs
activates the NLRP3 inammasome. PA correlates with ATP accumulation by affecting prominent mitochondrial function, resulting in
the abnormal accumulation of ROS (Fig. 4c).
PA induces dynamin-related protein 1 oligomerization (DRP1), which subsequently results in mitochondrial fragmentation and the
generation of mtROS [123]. Furthermore, SFAs stimulate CD36 receptors to downregulate the expression of electron transport chain
respiratory components [116] (Fig. 4d). In addition to its direct activation of the NLRP3 inammasome, mtROS induce mitochondrial
damage, resulting in the release of mitochondrial DNA into the cytoplasm and stimulation of the NLRP3 inammasome assembly
[124]. mtROS result in the dissociation of the TXNIP-TRX complex, whereby free TXNIP triggers the activation of the NLRP3
inammasome [117,118,125] (Fig. 4e). Beyond the capacity of mtDNA to trigger inammasome activation, mtDNA that has under-
gone ROS-mediated oxidation is equally capable of initiating this inammatory response [126]. Epigallocatechin-3-gallate is a
polyphenolic antioxidant extracted from green tea. It has the ability to reduce the production of mtROS in macrophages, thereby
decreasing oxidized mtDNA and suppressing the activation of the NLRP3 inammasome [127]. PA leads to mitochondrial dysfunction
by mediating autophagy dysfunction and ER stress [128,129]. For instance, the inactivation of AMPK by PA adversely affects auto-
phagy and stimulates the production of mtROS [128].
A decrease in the intracellular concentration of K
+
, caused by K
+
efux, is widely regarded as a common trigger for the NLRP3
inammasome activation. PA increases the saturation of phosphatidylcholine in the macrophage membrane, which contributes to
membrane and Na
+
-K
+
-ATP enzyme damage, thereby resulting in K
+
efux [130] (Fig. 4f). ROS generation is frequently accompanied
by K
+
efux [131]. The interplay between these pathways is currently unclear, but it is possible that low intracellular K
+
concentration
triggers ROS production or vice versa.
At present, therapy that targets the NLRP3 inammasome pathway appears to hold signicant promise. The pharmacological
inhibition of this pathway may prove particularly benecial for managing inammation during the intermediate and advanced stages
of AP. Liu et al. recently conducted a comprehensive review of existing literature on inhibitors that function by obstructing the for-
mation of the NLRP3 inammasome and proinammatory effector molecules [132]. Inhibitors that interact with FA receptors and
chelate FAs could potentially be effective strategies for mitigating AP inammation. For example, LC-UFAs, including eicosapentae-
noic acid (EPA), docosahexaenoic acid (DHA), and other family members, have been shown to inactivate the NLRP3 inammasome by
reducing both its priming and assembly through the GPR120 and GPR40 cell-surface receptors [133,134].
4.3. The regulatory effects of LC-UFAs on macrophages need to be further explored
The established anti-inammatory effect of LC-UFAs can effectively alleviate PA-induced macrophage activation at optimal con-
centrations. However, the anti-inammatory effect of LC-UFAs is concentration dependent. High concentrations of LC-UFAs can
decrease the integrity of the macrophage membrane, enhance DNA fragmentation and reduce mitochondrial transmembrane polar-
ization, eventually leading to macrophage death. The proportion of cells undergoing apoptosis has been negatively associated with the
LC-UFAs concentration, indicating limitations in managing the consequences of AP inammation [135]. However, research investi-
gating the inuence of LC-UFAs on macrophages remains limited. This research is crucial as alterations in the concentrations of UFAs
within peripancreatic tissue and serum may precipitate both early inammatory responses and subsequent anti-inammatory
reactions.
5. Lipid lowering therapy
Reducing circulating TGs and FAs during the initial stages of HTG-AP can be advantageous for patients. The standard treatment
protocol for HTG-AP typically incorporates the administration of brates, insulin, and heparin. Fibrates enhance lipoprotein lipase
(LPL) activity while diminishing hepatic TG synthesis [136]. Insulin stimulates LPL, facilitating the metabolism of chylomicrons and
very low-density lipoprotein, thereby reducing TG levels [137]. Furthermore, it inhibits HSL, which prevents the breakdown of TGs in
adipose tissue and the overproduction of FAs. Heparin has the potential to reduce lipids by augmenting the breakdown of TGs [138].
However, it does not exhibit an inhibitory effect on HSL, which can lead to an overproduction of FAs [32]. Consequently, clinicians
frequently employ a combination of these two methods. Plasmapheresis is another strategy for lipid reduction. However, its efcacy
remains a subject of ongoing debate [139,140]. A notable limitation of these studies is the absence of measurements of FA levels.
In the context of HTG-AP, there is an impairment in FA oxidation and lipotoxicity can be mitigated by reestablishing this process.
The administration of the neddylation inhibitor MLN4924 has been shown to restore pancreatic hnRNPA2B1 expression, thereby
restoring FA oxidation and cell proliferation in mice treated with HTG-AP [141]. Furthermore, enhancing hepatic metabolism of FAs
uptake can lead to a reduction in serum free FAs. PPARs play a signicant role in lipid metabolism. Fibrates stimulate PPAR-
α
, which
Q. Liu et al.
Heliyon 10 (2024) e31296
9
inhibits TG synthesis and accelerates FA oxidation, thereby contributing to their lipid-lowering effects. In the liver, PPAR-γ facilitates
FABP4-mediated uptake of free FAs and induces the expression of fatty acid synthase, further contributing to the reduction of serum
free FAs [142]. The application of rosiglitazone, a PPAR-γ agonist, demonstrates potential in the treatment of AP [143,144]. The
exploration of chelating agents tailored to specic FA isoforms, such as palmitoleic acid, presents a promising therapeutic avenue. The
presence of Ca
2+
in lactated Ringer solution has the capacity to chelate FAs, thereby reducing their concentration and subsequently
mitigating inammation. However, the clinical efcacy of lactated Ringer in treating AP remains a subject of debate [145–147]. The
lipase inhibitor orlistat, utilized in the treatment of obesity, has been shown to mitigate the severity of the AP inammatory response in
various animal models [29,148], However, clinical trials are not feasible due to its administration via intraperitoneal injection. The use
of LC-UFAs, such as omega-3 fatty acids, at an optimal dosage through oral or intravenous injection has demonstrated improved
prognosis in AP. Nevertheless, high concentrations of omega-3 fatty acids can lead to cytotoxicity [8].
The rapid reduction of lipids, while simultaneously preventing the overproduction of FAs, is essential for effective treatment. The
concentration changes in serum FAs can serve as a signicant indicator of treatment efcacy due to their cytotoxic properties.
6. Conclusion
Research suggests that during AP, pancreatic lipase degrades TGs in both peripancreatic fat and blood, thereby triggering systemic
inammation. FAs, which are produced as a result of TG hydrolysis, are recognized as key mediators of this inammatory response.
However, there is a notable lack of research investigating the correlation between lipase levels, FA levels, PACs, and macrophage
counts in patients with AP. This paper aims to offer a thorough review and analysis of existing research in relation to these factors.
PNLIP is believed to contribute to the deterioration of AP by breaking down peripancreatic fat. However, the onset and progression
of AP are also inuenced by adipose ATGL and HSL. For instance, the catabolism of TGs in adipose tissue can lead to high concen-
trations of UFAs. This process may be a key pathogenic mechanism underlying obesity-alcoholic pancreatitis. This article provides a
comprehensive summary of the pathogenic pathways associated with high concentrations of LC-UFAs in PACs. It delves into an un-
explored pathway that triggers Ca
2+
overload. Additionally, it scrutinizes the mechanism through which UFAs induce acinar cell
death. The review also discusses the impact of elevated LC-UFAs concentrations on the functionality and activity of macrophages. The
deleterious effects of PA on PACs may be intensied in the presence of pathogenic factors associated with AP, potentially elucidating
the susceptibility and severity of pancreatitis in obese patients. The activation of macrophages by PA is a pivotal element in the in-
ammatory response. The paper concludes with an overview of potential therapeutic agents for HTG-AP (Table 1). It should be
highlighted that the concentration of FAs in serum signicantly inuences AP development, alongside TGs. The key to managing
inammation lies in limiting excessive FA production while swiftly reducing lipids. However, our study does not address more FA
isoforms. Maria et al. delineate the differential proinammatory and anti-inammatory impacts of various FA isoforms on macro-
phages [101]. Recent research indicates that early serum palmitoleic acid levels in AP patients correlate with organ failure [149].
Furthermore, short-chain and medium -chain fatty acids are also crucial for the development of AP. Investigating FAs and their iso-
forms could provide insights into the pathogenesis of AP and facilitate the development of effective treatments.
Author declaration form
The construction of the main framework: QL, ZH, XG, YG. Collection of references: HZ, QL, ZH. Write manuscript: QL, ZH Critical
revision of the manuscript: QL, JY. Drawing schematic diagram: XG, YG. All authors approved the nal version of the manuscript.
Table 1
The table lists potential therapeutic agents and their mechanisms of action for HTG-AP.
DRUG TYPE THERAY PATHWAY PMID
Galactose Carbohydrate Supply extra ATP via glycolysis cycle 29893744
Melatonin Hormone Upregulate SERCAs expression to improve Ca
2+
overload 22687382
Rapamycin Macrolide antibiotic Improve autophagy and ER stress by inhibiting mTOR 32642911
Trehalose Carbohydrate Enhance autophagy efciency 29907758
Omega-3 PUFAs Unsaturated fatty
acids
Inhibit the activation of NLRP3 inammasome by inhibiting GPR120 and GPR40 receptor 23809162
Orlistat Lipase inhibitor Inhibit the breakdown of TGs in blood and peripancreatic fat 25579844
Urolithin A Polyphenols restore the balance of mitochondrial fatty acid oxidation metabolism 38116065
Resveratrol Polyphenols Increase the expression of SIRT3 and reduce the generation of ROS 33628394
Chlorogenic acid Polyphenols Reduced the serum and pancreatic levels of macrophage migration inhibitory factor 28919396
Epigallocatechin-3-gallate Polyphenols Reduce the production of mtROS and suppress the activation of the NLRP3 inammasome
in macrophages
34018522
N(1), N(11)-
diethylnorspermine
Polyamine analog Prevent the premature trypsinogen activation 21814793
Bismethylspermine Polyamine analog Prevent the premature trypsinogen activation 16400014
Spermidine Spermidine Inhibit mTOR and activate AMPK 21831529
Q. Liu et al.
Heliyon 10 (2024) e31296
10
Funding
This work was supported by the National Natural Science Foundation of China (Grant No. 82000516); the Zhejiang Province’s Key
R&D Plan Project (Grant No. 2023C03054 and 2024C03048); the Natural Science Foundation of Zhejiang Province (Grant No.
LQ24H030008); the Zhejiang Medical and Health Science and Technology Plan (Grant Nos. 2022RC056, 2020KY703 and
2023RC229); the Zhejiang Chinese Traditional Medicine Scientic Research Fund Project (2022ZB271); and the Construction Fund of
Medical Key Disciplines of Hangzhou (OO20190001).
Data availability
No data was used for the research described in the article.
CRediT authorship contribution statement
Qiang Liu: Supervision. Xinyi Gu: Supervision, Investigation. Xiaodie Liu: Investigation. Ye Gu: Investigation. Hongchen Zhang:
Investigation. Jianfeng Yang: Writing – review & editing. Zhicheng Huang: Writing – review & editing, Writing – original draft.
Declaration of competing interest
The authors declare that they have no known competing nancial interests or personal relationships that could have appeared to
inuence the work reported in this paper.
Acknowledgments
We are grateful to all members of the Department of Gastroenterology of Afliated Hangzhou First People’s Hospital. We thank the
members of the Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province for providing technical
assistance.
Abbreviations
AMPK AMP-activated protein kinase
ATGL Adipose triglyceride lipase
CEL Carboxyl ester lipase
CD36 Cluster of differentiation 36
CN Calcineurin
CypD Cyclophilin D
DAGs Diacylglycerols
DHA Docosahexaenoic acid
ER Endoplasmic reticulum
EPA Eicosapentaenoic acid
FABP4 Fatty acid-binding protein 4
FAEEs Fatty acid ethyl esters
FAs Fatty acids
HSL Hormone-sensitive lipase
HTG-AP hypertriglyceridemia-induced acute pancreatitis
IP3R Inositol 1,4,5-trisphosphate receptor
LCFAs Long-chain fatty acids
LC-SFAs Long-chain saturated fatty acids
LC-UFA Long-chain unsaturated fatty acid
LPL lipoprotein lipase
mTOR Mammalian target of rapamycin
MPTP Mitochondrial permeability transition pore
OA Oleic acid
LA Linoleic acid
PA Palmitic acid
PACs Pancreatic acinar cells
PPARγ Peroxisome proliferator-activated receptor
PMCAs Plasma membrane Ca
2+
channels
PKC Protein kinase C
PNLIP Pancreatic triacylglycerol lipase
ROS Reactive oxygen species
Q. Liu et al.
Heliyon 10 (2024) e31296
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RyR Ryanodine receptor
SERCAs Smooth ER Ca
2+
channels
SFAs Saturated fatty acids
SIRT3 sirtuin 3
UCP2 uncoupling protein 2
TXNIP Thioredoxin-interacting protein
TGs Triglycerides
UFAs Unsaturated fatty acids
3-BCP 3-benzyl-6-chloro-2-pyrone.
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