Induction of hyperlipidemic pancreatitis by different fatty acids: A narrative review

Abstract

Epidemiological evidence suggests that there is a direct relationship between the degree of obesity and acute pancreatitis severity. Intake of different fatty acids leads to different types of hyperlipidemias. Adipose degradation by pancreatic lipase generates different free fatty acids, which can exacerbate pancreatitis. Saturated fatty acids (SFAs) play an inflammatory role in human metabolic syndrome and obesity, whereas unsaturated fatty acids (UFAs) are “good fats” that are thought to enhance overall health status. However, it appears that serum UFAs correlate with severe acute pancreatitis. Additionally, the “obesity paradox” suggests that UFAs potentially minimize direct harm to the organ. This review provides an in-depth overview of the role of SFAs and UFAs in acute pancreatitis of hyperlipidemia and discusses potential prevention targets for severe acute pancreatitis.

Key Words: Severe acute pancreatitis; Hypertriglyceridemia; Saturated fatty acid; Unsaturated fatty acid; M1 macrophage polarization

Core Tip: This review explores the potential causes of hyperlipidemic pancreatitis. The increased intake of saturated fatty acids (SFAs) initially elevates pancreatic lipase activity, accelerating lipolysis and fat necrosis, which in turn increases free fatty acids levels and creates a permissive inflammatory environment in severe acute pancreatitis. This process accelerates immune response of M1 macrophage polarization and subsequent acinar damage. Over time, unsaturated fatty acids (UFAs) exacerbate acinar cell damage and impair β-cell function in the pancreas, leading to diabetes. This cumulative effect is a consistent and damaging process. Therefore, the ratio of UFAs to SFAs is crucial in the pathogenesis of severe acute pancreatitis, and the progression is complex. It is essential to clearly define the primary roles of SFAs and UFAs in the development of severe acute pancreatitis.

INTRODUCTION

Acute pancreatitis (AP) is a rapid-onset inflammatory disease marked by the self-digestion of pancreatic tissue, which can cause both local pancreatic damage and a systemic inflammatory response[1]. Although the biological mechanisms underlying AP are not fully understood, gallstones and chronic alcohol consumption are recognized as predominant etiologies of AP, with hypertriglyceridemia being the third most common cause. Although hypertriglyceridemia-induced pancreatitis (HTGP) accounts for approximately 5% of all AP cases, its reported prevalence can be as high as 22% and it may be responsible for up to 56% of cases during pregnancy[2]. HTGP pathophysiology is associated with the accumulation of free fatty acids (FFAs) and activation of the inflammatory response[3]. Researchers have suggested that FFA release is related to the onset and severity of AP[4]. Circulating FFAs differ in their saturation level [saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs), or polyunsaturated fatty acids (PUFAs)], as well as in their carbon chain length, (short-, medium-, and long-chain). These FFAs have been implicated in AP pathogenesis by contributing to systemic inflammatory response syndrome (SIRS), multiple organ dysfunction, and circulatory shock[4]. Specifically, FFAs can trigger the activation of trypsinogen to initiate AP[5]. In addition, FFAs exert cytotoxic and proinflammatory effects that contribute to adipose tissue (AT) injury and necrosis. Notably, AT necrosis has been frequently observed in cases of severe AP (SAP)[6].

In this review, we provide a detailed overview of the role of different FFAs in AP, particularly in the context of coexisting obesity and hyperlipidemia. Furthermore, we summarize inflammatory states, levels of AT necrosis, and alterations in carbohydrate and lipid metabolism in AP induced by high fat diets. Finally, we seek to elucidate the key roles of saturated and unsaturated fatty acids (UFAs) in modulating AP progression and severity, with the overall aim of providing recommendations for lifestyle modifications that effectively reduce the risk of AP onset.

OXIDATIVE AND ER STRESS IN HIGH FAT DIET-INDUCED AP

AP is an acute inflammatory disease of the digestive system. Elevated concentrations of FFAs in plasma following high-fat dietary intake is a common feature of inflammatory diseases, including AP[7]. Although AP pathogenesis is not fully understood, oxidative stress is widely considered a key mechanism in its early development. Oxidative stress results from a disruption to the balance between pro-oxidant and antioxidant systems, leading to inflammatory cell recruitment and activation, which in turn amplify both oxidative stress and inflammation through a positive feedback loop[8]. Gulhane et al[9] demonstrated that a high-fat diet (HFD) induced the expression of genes associated with endoplasmic reticulum (ER) stress, including key markers of the unfolded protein response (UPR) pathway, such as spliced X-box binding protein 1, the ER chaperone glucose-regulated protein 78, and the ER-associated degradation component Edem1. Oxidative stress impairs ER functionality, leading to the initiation of the UPR, a tightly regulated signaling network that aims to re-establish proteostasis and prevent intracellular accumulation of aberrant polypeptides. This adaptive response involves the induction of ER-resident chaperones, transient suppression of protein synthesis to alleviate translocation burden, and promotion of retrotranslocation mechanisms that export defective proteins to the cytoplasm for ubiquitin tagging and subsequent degradation via lysosomal pathways[10]. ER dysfunction has been associated with activation of inflammatory signaling modules, including the IκB kinase (IKKβ) and c-Jun N-terminal kinase (JNK) axes, upregulation of the transcription factor CREB-H, and increased reactive oxygen species (ROS) generation[11]. During inflammation, factors such as dysregulated adipokine secretion, AT expansion, and elevated SFAs further exacerbate ER stress, perpetuating a self-amplifying cycle of inflammation[12-15].

Regardless of etiology, injury to pancreatic acinar cells leads to the leakage of digestive enzymes, such as lipases and phospholipase A2, into the pancreatic interstitium and systemic circulation[16]. Lipolytic activity on peripancreatic AT results in the release of large quantities of FFAs. This process is closely associated with multisystem organ failure in SAP, particularly in the context of obesity[17]. In experimental settings, both total lipid extracts and individual FA fractions derived from necrotic AT enhance the expression of proinflammatory mediators in pancreatic acinar cells. In rat models of AP, peripancreatic fat necrosis is characterized by a predominance of SFAs, particularly palmitic acid (PA, C16:0) and stearic acid (SA, C18:0), while oleic acid (OA, C18:1) and linoleic acid (LA, C18:2) constitute the major UFAs present in affected tissue[18]. However, the specific contributions of individual FAs to the initiation and propagation of inflammatory responses in acinar cells remain unclear. The harmful effects of FAs have been attributed to their cytotoxic properties, particularly their ability to disrupt cellular membranes, as well as their role in promoting inflammatory signaling pathways[19,20]. Excessive dietary fat intake stimulates mitochondrial β-oxidation of FFAs, leading to increased ROS production, which in turn contributes to the initiation of proinflammatory responses[21,22]. Interestingly, while clear proinflammatory effects have been associated with SFAs[23], both pro- and anti-inflammatory effects have been reported for UFAs[24-26]. These conflicting findings may be attributed to cell-type-specific responses and the distinct biological effects of individual fatty acids, which vary according to their chemical structure. To mechanistically explain the effects of UFAs and SFAs, Mateu et al[27] investigated key intracellular signaling pathways involved in the inflammatory response of pancreatic acinar cells. Their findings demonstrated that c-JNK, extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinases (p38-MAPKs), and Janus kinase (JAK) are critical upstream regulators of C-C motif chemokine ligand 2 (CCL2; also known as monocyte chemoattractant protein-1, MCP-1) expression induced by the UFAs OA and LA. These results highlight the necessity of evaluating the distinct effects of individual UFAs and SFAs on a uniform cell type, as well as elucidating the molecular mechanisms that mediate their inflammatory actions.

DISTINCT EFFECTS OF FATTY ACIDS BROKEN DOWN BY PANCREATIC LIPASE IN ACUTE HYPERLIPIDEMIC PANCREATITIS

Triglycerides are the primary chemical form in which fat is stored in the body. Structurally, they consist of three fatty acids chains attached to a single glycerol molecule. Patients with HTG-AP typically present 10-15 years earlier than those with AP of other etiologies. Approximately two-thirds of HTG-AP cases occur in males, and patients with HTG-AP also tend to have higher body mass indexes[28]. Notably, triglycerides themselves are not directly responsible for initiating AP. Rather, it is their hydrolysis by lipase into FFAs, particularly when concentrations of UFAs are sufficiently elevated, that leads to acinar cell injury. This injury is mediated through trypsin activation and a dose-dependent increase in cytosolic calcium levels, a process influenced by the ratio of UFAs to SFAs, ultimately contributing to pancreatitis.

Ingested triglycerides cannot be directly absorbed by the small intestine without prior digestion. Within the jejunum, pancreatic lipase (PNLIP) catalyzes the breakdown of triglycerides into FFAs and glycerol, which are subsequently taken up by intestinal epithelial cells. Following translocation across the intestinal barrier, FFAs are re-esterified with glycerol to reform triglycerides. These resynthesized lipids are incorporated into chylomicron-lipoprotein complexes composed of triglycerides, cholesterol, phospholipids, and apolipoproteins (APOs). Chylomicrons are secreted into the lymphatic system via the thoracic duct and eventually enter the systemic circulation. Once in the bloodstream, they serve as transport vehicles, delivering lipid constituents to peripheral tissues such as skeletal muscle, cardiac tissue, and the liver for further metabolism. Lipoprotein lipase (LPL), a key hydrolytic enzyme localized to the endothelial surface of capillaries in adipose and muscle tissue, is primarily synthesized as a precursor protein by adipocytes and myocytes. Lipase maturation factor 1 facilitates proper LPL folding and maturation, which is subsequently secreted into the interstitial space, transported across the endothelium, and anchored to the luminal surface by glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1. LPL activity is tightly regulated by a variety of apolipoproteins (APOs) and angiopoietin-like proteins, with apolipoprotein C-II (APOC2), APOC3, APOA5, apolipoprotein E (APOE), ANGPTL3, ANGPTL4, and ANGPTL8 playing particularly critical roles. APOC2 is an essential cofactor required for LPL activation, and APOE is a key ligand in the hepatic clearance of triglyceride-rich lipoproteins[29]. Conversely, ANGPTL proteins predominantly function by inhibiting LPL activity through paracrine or endocrine mechanisms, and their expression is influenced by systemic nutritional, metabolic, and hormonal signals.

Enzymatic defects in lipid metabolism can lead to significantly elevated blood lipid levels, a condition known as primary hypertriglyceridemia. Under normal physiological conditions, FFAs hydrolyzed from triglycerides bind to albumin, rendering them nontoxic. However, when serum triglyceride levels become excessively high, the binding capacity of albumin is exceeded, resulting in the accumulation of unbound FFAs[30]. These unbound FFAs are cytotoxic and contribute to AP pathogenesis in severe HTG. In particular, FFAs exert proinflammatory effects that damage pancreatic acinar cells and vascular endothelium. In an acidic microenvironment, FFAs can activate trypsinogen, initiating premature enzyme activation within the pancreas and triggering local inflammation[31]. This sets off a self-amplifying cascade involving the release of inflammatory mediators and ROS, which can lead to tissue edema, necrosis, and widespread pancreatic injury if unresolved[32]. In advanced stages, necrotizing pancreatitis can trigger SIRS, frequently leading to multiorgan dysfunction, protracted clinical courses, or mortality[33]. Although the exact pathophysiological mechanisms linking elevated serum triglycerides to the onset of AP remain incompletely elucidated, the prevailing theory, first articulated by Havel in 1969, proposes that in the context of pronounced HTG, excessive accumulation of large lipoprotein particles such as chylomicrons compromises capillary microcirculation, thereby exacerbating pancreatic injury[34]. When such events are localized to the pancreas, reduced perfusion leads to ischemia and creates an increasingly acidic microenvironment in the acinar tissue. Under these conditions, PNLIP leaks from damaged acinar cells and hydrolyzes surrounding triglycerides, resulting in FFA accumulation, which exacerbates pancreatic injury and inflammation. Notably, experimental models of HTG and AP have demonstrated that FFAs also enhance Protein Kinase C (PKC) activity, further contributing to the pathophysiological cascade[35]. High UFA concentrations can mimic the effects of CCK at supraphysiological levels by activating specific PKC isoforms, including PKC-α, -δ, and -ζ, suggesting that hyperlipidemic pancreatitis (HLP) may be partially mediated through UFA-induced PKC activation[5]. Cui et al[36] found that FFAs promote ER stress in pancreatic β cells by enhancing calcium influx, leading to β cell dysfunction and apoptosis. Similarly, in an arginine-induced experimental model of AP, ER stress signaling pathways were activated early in pancreatic acinar cells[37]. Moreover, hypertriglyceridemia exacerbates ER stress[38]. These findings highlight the need for continued research into the impact of elevated UFA concentrations on critical cellular pathways implicated in AP pathogenesis. Key processes warranting further investigation include calcium mobilization from acidic organelles, mitochondrial dysfunction, ER stress, dysregulated autophagy, impaired intracellular trafficking, and aberrant lysosomal and secretory responses. Notably, Navina et al[23] demonstrated that UFAs elevate intracellular calcium concentrations [ic (Ca²⁺)], inhibit mitochondrial complexes I and V, and induce necrosis in pancreatic acinar cells, contributing to tissue inflammation. In contrast, SFAs did not elicit these deleterious effects. UFAs have also been shown to directly influence pancreatic ductal cell function and ion channel protein expression. Although SFAs are less acutely cytotoxic, long-term exposure can affect pancreatic ductal cell plasticity, promoting their transdifferentiation into adipocytes or insulin-producing β-cells[39]. Prolonged lipotoxic stress from high concentrations of FAs can also stimulate insulin production and leptin release from pancreatic ductal cells, as observed in palmitate-treated rat ductal cell lines. Furthermore, HFD elevates serum triglyceride and FFA levels in experimental animals and alters pancreatic ductal function. Consistent with this notion, Huang et al[40] demonstrated that HFD can promote pancreatic ductal epithelial cell transdifferentiation into insulin-producing phenotypes.

Lipases constitute a family of enzymes responsible for the hydrolysis of triglycerides into FFAs and glycerol. These lipases are differentially expressed across various tissues: hepatic lipase in the liver, hormone-sensitive lipase in adipocytes, LPL on the vascular endothelium, and PNLIP in the small intestine[41]. PNLIP plays a critical role in dietary fat digestion and the absorption of fat-soluble vitamins[42]. During AP, PNLIP is released in an uncontrolled manner into the circulation and surrounding visceral AT. This results in FFA generation from both circulating triglycerides and damaged adipocytes due to the aberrant activity of PNLIP following acinar cell injury[43,44]. Excessive levels of FFAs, particularly those not bound to albumin, can exert direct lipotoxic effects by integrating into cellular membranes and interacting with other biomolecules, thereby promoting cell death and cytokine release[23,45]. Among FFAs, UFAs have been more strongly associated with organ failure in AP animal models compared to their saturated counterparts[44]. The higher reactivity of UFAs due to their double bonds may contribute to their greater cytotoxic potential. While some UFAs (e.g., ω-3 and ω-6) exhibit anti-inflammatory properties under physiological conditions, others have been implicated in exacerbating AP pathogenesis[46,47]. Clinical studies support this distinction. For instance, one investigation found that serum saturated:unsaturated FFA ratio was significantly lower in AP patients compared to healthy controls[17]. A separate study demonstrated that necrotic pancreatic collections contained elevated levels of both UFAs and SFAs. Notably, UFAs, particularly oleic and LA, induced acinar cell necrosis at concentrations less than half of those detected in the necrotic material, whereas SFAs failed to elicit necrosis even at twice those levels[44]. Furthermore, LA exhibited greater cytotoxicity than PA, as evidenced by increased lactate dehydrogenase release and impaired mitochondrial function in acinar cells[23]. Collectively, these findings indicate that while not all UFAs exert harmful effects, specific subtypes may play a pivotal role in FFA-mediated pancreatic injury during AP.

SFAs ACCELERATE ADIPOSE TISSUE NECROSIS IN ACUTE HLP

Obesity is an independent risk factor for increased severity in AP[48] Although the association between obesity and increased severity of AP is well recognized, the underlying mechanisms remain incompletely understood. Fat necrosis can arise through both enzymatic and non-enzymatic pathways[49]. While non-enzymatic fat necrosis is commonly associated with traumatic events such as direct physical injury, enzymatic fat necrosis is typically observed in AP following aberrant PNLIP activity[49]. Obesity leads to AT accumulation, especially visceral fat. Similarly, increased fat accumulation within the pancreas, referred to as fatty pancreas or pancreatic steatosis, has been frequently observed in individuals with obesity. However, our current understanding of the clinical implications and pathophysiological consequences of pancreatic fat deposition remains limited and largely speculative[50]. During AP, saponification of peripancreatic fat is a common pathological event. This process occurs because of adipocyte injury, leading to uncontrolled PNLIP release, subsequent triglyceride hydrolysis, and FFA liberation. Being negatively charged, FFAs readily bind to positively charged calcium ions in the extracellular environment, forming insoluble calcium soaps, a process termed saponification[51]. SAP carries a high mortality rate[52], which appears to be exacerbated by the presence of obesity regardless of underlying etiology. A human autopsy study of individuals who succumbed to SAP identified a positive correlation between intra-pancreatic fat (IPF) content and the extent of pancreatic necrosis[23]. Supporting this clinical observation, in vitro analyses demonstrated that UFAs released from IPF exert both proinflammatory and cytotoxic effects on pancreatic acinar cells by triggering intracellular calcium overload and inhibiting mitochondrial complexes I and V[23]. Complementary findings from animal models further revealed the accumulation of intra-acinar fat in obese mice, implicating ectopic lipid deposition within the pancreas as a potential driver of disease progression in obesity[53,54]. In a pilot study, we found that a higher intake of SFAs led to increased pancreatic fat in mice, as well as more fat necrosis and saponification, which was evident in the pancreas and retroperitoneal area.

High SFA has been linked to enhanced lipid accumulation in both hepatic and visceral compartments, whereas PUFA-rich diets are linked to greater lean body mass accrual[55]. These findings underscore the significant impact of dietary fat composition on metabolic health. Nevertheless, the molecular mechanisms by which overfeeding and varying fatty acid profiles influence lipid accumulation and metabolism remain incompletely understood. Emerging evidence from both animal and human studies suggests that excessive fatty acid intake can modulate the epigenetic landscape of AT[56,57]. However, data from randomized, food-based intervention trials are scarce. To date, only a few studies have reported epigenetic changes in response to lipid supplementation in human blood samples, with limited insight into adipose-specific effects[58-61]. Despite inducing comparable weight gain, SFA overfeeding led to a greater increase in liver fat and visceral adiposity than PUFA overfeeding. These divergent metabolic outcomes may, in part, be explained by epigenetic modifications. Indeed, recent data indicate that both SFA and PUFA overfeeding can alter the epigenome of human AT, potentially contributing to the distinct metabolic phenotypes observed during in vivo dietary interventions. Interestingly, only SFA overfeeding has been reported to significantly alter gene expression in AT, including that of acyl-CoA oxidase 1[62].

AT harbors a significant immune cell population, which actively contribute to systemic inflammation by secreting cytokines and other inflammatory mediators into circulation. Among immune cell populations, two principal macrophage subsets serve as key inflammation modulators: classically activated M1 and alternatively activated M2 macrophages[63]. M1 polarization is typically driven by Th1-type cytokines, including interferon-γ and granulocyte-macrophage colony-stimulating factor, or by the recognition of pathogen-associated molecular patterns (PAMPs) like lipopolysaccharide (LPS). These proinflammatory macrophages secrete cytokines including tumor necrosis factor α (TNF-α), IL-1β, and IL-6[64]. In contrast, M2 macrophages are induced by Th2-type mediators, primarily IL-4, IL-10, and IL-13. They are associated with anti-inflammatory and tissue-repair functions. Their roles include facilitating efferocytosis, promoting regulatory T cell (Treg) differentiation, and secreting immunomodulatory cytokines such as IL-10 and transforming growth factor-β (TGF-β). An imbalance in M1/M2 polarization has been implicated in the development and persistence of various chronic inflammatory diseases. To explore the role of obesity in SAP, Han et al[65] established an HFD-induced obesity model in rats. Their study demonstrated a significant increase in serum non-esterified fatty acid levels and a marked shift toward M1 macrophage polarization within AT. These findings suggest that obesity exacerbates inflammatory responses in SAP by enhancing lipotoxicity and altering immune cell phenotypes.

Early recruitment of inflammatory monocytes into pancreatic tissue during AP is critically dependent on CCL2. Experimental studies in rodent models have shown that pharmacological inhibition of CCL2 or its receptors, including CCR2, ACKR1, and ACKR2, attenuates disease severity[66]. Upon infiltration, these monocytes differentiate into classically activated M1 macrophages, amplifying the inflammatory cascade. In contrast, pancreatic tissues from patients with chronic pancreatitis (CP) exhibit increased infiltration of alternatively activated M2 macrophages[67], which are implicated in fibrogenesis via pancreatic stellate cell activation. These findings highlight distinct macrophage polarization patterns in AP vs CP. Macrophages are central mediators of AT inflammation, and shifts in their polarization states are strongly associated with metabolic dysregulation, obesity, and insulin resistance. In both humans with obesity and HFD-induced obese mouse models, macrophage accumulation in AT is characterized by a shift from the anti-inflammatory M2 phenotype toward the pro-inflammatory M1 phenotype[68-70]. This phenotypic switch correlates with heightened AT inflammation and systemic insulin resistance[71]. Recent studies have identified interferon regulatory factor 3 (IRF3) as a pivotal transcriptional regulator in HFD-induced inflammation. Kiran et al[72] demonstrated that IRF3, together with TGF-β1 and STAT3 signaling pathways, downregulates peroxisome proliferator-activated receptor gamma (PPARγ) expression in AT, thereby sustaining chronic low-grade inflammation. Additionally, enhanced infiltration of Th17 cells and dendritic cells within AT contributes to M1 macrophage polarization and disrupts the Th17/Treg equilibrium, further propagating metabolic inflammation. Decreased PPARγ expression in obesity may exacerbate this immune imbalance by impairing Th17/Treg homeostasis[73]. PPARγ, a ligand-activated nuclear receptor, plays an essential role in regulating lipid metabolism and inflammatory responses[74]. It is highly expressed in both pancreatic acinar cell lines (e.g., AR42J cells) and native pancreatic tissue[75,76]. ω-3 PUFAs are natural PPARγ agonists and have been shown to attenuate inflammation[77]. Conversely, FAs can interfere with PPARγ's anti-inflammatory effects, promoting inflammation through activation of MAPKs, JAK, nuclear factor-κB (NF-κB), and STAT3 pathways. In turn, PPARγ activation suppresses these signaling cascades. Collectively, these findings support the therapeutic potential of PPARγ agonists in mitigating AP and obesity-associated inflammation[78-80].

SFAs INCREASE THE INFLAMMATION RESPONSE OF TOLL-LIKE RECEPTOR 4-MEDIATED AUTOPHAGY IN ACUTE HLP

Toll-like receptors (TLRs) are type I transmembrane proteins that play a pivotal role in innate immune response initiation and propagation during inflammation[81]. Among pattern recognition receptors, TLR4 detects a broad spectrum of exogenous ligands and transduces extracellular danger signals into intracellular proinflammatory responses[82]. It is widely expressed in immune cells, including monocytes, macrophages, and Kupffer cells, as well as in non-immune cells such as intestinal epithelial and endothelial cells, adipocytes, hepatocytes, and pancreatic acinar cells[83]. One of the most well-characterized ligands of TLR-4 is LPS, which interacts with the LPS-binding protein and its co-receptor, cluster of differentiation 14, to activate TLR4. This ligand-receptor complex triggers a downstream signaling cascade involving focal adhesion kinase activation, facilitating the recruitment of myeloid differentiation primary response gene 88 and interleukin (IL)-1 receptor-associated kinase 4. These events culminate in the NF-κB and MAPK pathway activation[84-88], leading to proinflammatory gene upregulation, including TNF-α, IL-6, iNOS, and MCP-1[89]. A secondary activation signal promotes the assembly of inflammasome complexes (e.g., NLRP3), enabling the cleavage of pro-cytokines into their mature, active forms. This dual-signal mechanism underscores the central role of innate immune activation in amplifying pancreatic inflammation.

In individuals with genetic susceptibility, recurrent pancreatic injury promotes the release of damage-associated molecular patterns (DAMPs), including fibronectin extra domain A (fibronectin-EDA) and tenascin-C, which further amplify innate immune activation. These endogenous molecules act as danger signals and are sensed by TLR4 expressed on resident immune and stromal cells. TLR4 activation not only amplifies fibrogenic gene expression and promotes myofibroblast differentiation but also enhances fibroblast sensitivity to transforming TGF-β, thereby contributing to tissue remodeling and fibrosis. Moreover, TLRs function as key sensors of both DAMPs and PAMPs within pancreatic cells. Upon activation, TLRs initiate canonical inflammatory signaling pathways, most notably the nuclear NF-κB cascade, culminating in the transcriptional induction of proinflammatory cytokine precursors, including pro-IL1β and pro-IL18[90]. Interestingly, in the context of AP, TLR4 is highly expressed in pancreatic tissue. Experimental models have shown that genetic deletion or pharmacological inhibition of TLR4 reduces acinar cell necrosis and attenuates disease severity[91,92]. It is also implicated in regulating chemokine production, neutrophil infiltration, and tissue injury in SAP[93]. Although AP may be initially triggered by intra-acinar events, such as premature trypsinogen activation, its progression and severity are predominantly influenced by subsequent inflammatory and immunometabolism responses. These processes are driven by innate immune pathways, including TLR-mediated signaling and inflammasome activation, underscoring their potential as key therapeutic targets.

In addition to its proinflammatory role, TLR4 has been increasingly recognized as a trigger of necroptosis, a regulated form of necrotic cell death characterized by the activation of receptor-interacting protein kinase 1 (RIP1), RIP3, and mixed lineage kinase domain-like pseudokinase[94]. Unlike apoptosis, necroptosis elicits a robust inflammatory response due to intracellular DAMP release. In models of severe experimental pancreatitis, necroptosis is the dominant mode of acinar cell death[95]. Notably, an inverse correlation between RIP1 and RIP3 expression levels have been reported in AP mouse models[96]. Emerging evidence further implicates TLR4-mediated necroptosis in the pathogenesis of inflammatory diseases, including AP[97,98].

Recent research suggests that SFAs can act as endogenous TLR4 ligands, thereby promoting inflammatory responses. Lipid A, a component of LPS, contains saturated acyl chains that are essential for TLR4 activation, supporting the notion that saturated lipid moieties can engage this receptor[99,100]. Besides LPS, several endogenous molecules-such as heat shock proteins (Hsp60, Hsp70), the type III repeat extra domain A of fibronectin, hyaluronic acid fragments, heparan sulfate polysaccharides, and fibrinogen-have been identified as TLR4 ligands[101]. In 2001, Lee et al[102] demonstrated that SFAs directly induced inflammatory gene expression via TLR4 signaling in vitro. Notably, fibrinogen, an acute-phase reactant elevated during obesity, can activate TLR4, thereby amplifying systemic inflammation[103]. Consistent with these findings, Kim et al[104] showed that TLR4-deficient mice failed to mount a proinflammatory cytokine response upon HFD exposure, highlighting the centrality of TLR4 in mediating HFD-induced inflammation. Furthermore, a proposed feedback loop suggests that RIP3-dependent necroptosis augments TLR4-driven inflammation through the induction of cytokines such as TNF-α via NF-κB signaling.

Among SFAs, lauric acid (C12:0) has the highest potential to activate COX-2 expression through NF-κB in macrophage cell lines, followed by PA (C16:0) and SA (C18:0)[102]. Palmitate activation of TLR4 was associated with increased JNK and IKK-β phosphorylation and elevated proinflammatory cytokine secretion[105]. In contrast, neither monounsaturated nor PUFAs activated TLR4. Interestingly, pretreatment with ω-3 PUFA docosahexaenoic acid (DHA; C22:6, ω-3) or OA (ω-9) significantly attenuated the lauric acid-induced inflammatory response in vitro[102]. PUFAs, particularly eicosapentaenoic acid (EPA; C20:5, ω-3) and DHA, modulate inflammation by acting as precursors for anti-inflammatory eicosanoids and by directly suppressing inflammatory gene expression in macrophages, including COX-2, iNOS, and IL-1β[102,106]. These ω-3 PUFAs also inhibit the TLR4-induced NF-κB pathway[102,107,108]. Mechanistically, EPA and DHA bind to PPARs, notably PPAR-α, PPAR-γ, and PPAR-β/δ, which heterodimerize with retinoid X receptor and interact with peroxisome proliferator response elements in the promoter regions of lipid metabolism and anti-inflammatory genes[109]. Moreover, EPA and DHA inhibit NADPH oxidase activity, thereby reducing ROS production, which is essential for TLR4 recruitment into lipid rafts and subsequent dimerization and activation[110]. Incorporation of DHA into the plasma membrane can further disrupt lipid raft formation, reducing TLR4 surface localization and downstream NF-κB activation[110-112]. These findings underscore the differential immunomodulatory roles of SFAs and PUFAs, with implications for dietary interventions in inflammatory diseases such as obesity-related AP.

OVERCONSUMPTION OF SFAs AND INCREASED GUT PERMEABILITY IN AP

HFD-induced dysbiosis is linked to a range of molecular abnormalities, with disruption of gut barrier function being particularly critical. Like the airways and genitourinary tract, the gastrointestinal tract serves as a semipermeable barrier, facilitating nutrient absorption while preventing the translocation of harmful antigens and microorganisms from the gut lumen. Intestinal barrier integrity is preserved by a complex system involving the gut microbiota, a protective mucus layer, the epithelium, and immune cells within the lamina propria and submucosa[113]. The process of intestinal fatty acid absorption involves two distinct steps: (1) Intraluminal fatty acid entry into intestinal absorptive epithelial cells (uptake); and (2) The transfer of absorbed fatty acids into the lymphatic circulation, specifically the thoracic duct (absorption)[114]. In experimental models, intraduodenal infusion of emulsified fatty acids into rats, consisting of 14C-labeled PA or LA mixed with monoolein and taurocholate, demonstrated significant differences in absorption efficiency. PA consistently required a longer intestinal length for complete absorption than LA[115]. Furthermore, although mucosal uptake of both fatty acids was similar in short-term settings, palmitate esterification was significantly less efficient than that of linoleate. These findings suggest that saturated fats exert localized effects on the intestinal mucosa before being systemically metabolized by peripheral organs such as AT, liver, or skeletal muscle. Therefore, early exposure of the gut barrier to SFAs may initiate a cascade of barrier dysfunction, immune activation, and dysbiosis, contributing to systemic inflammation and metabolic impairment.

Excessive SFA consumption is associated with adverse health effects[116]. Even short-term overconsumption of SFAs can trigger low-grade inflammation and initiate intracellular damage, laying the groundwork for obesity and its associated comorbidities[117-119]. Emerging evidence indicates that disruption of the gut-pancreas axis plays a central role in SAP pathogenesis. For instance, Li et al[120] demonstrated that HFD induces dysbiosis characterized by the overgrowth of pathogenic genera such as Escherichia-Shigella, Enterococcus, and Klebsiella, which significantly exacerbates pancreatic injury. In contrast, certain UFAs have anti-inflammatory potential through the activation of specific G-protein-coupled receptors. GPR120 (also known as the ω-3 fatty acid receptor) and GPR40 are selectively activated by long-chain fatty acids, predominantly ω-3 and ω-9 species like DHA and OA, respectively[121]. Both receptors signal through the Gq protein family, leading to increased concentrations of intracellular calcium. GPR40 is predominantly expressed in pancreatic β-cells, where its activation by long-chain fatty acids enhances glucose-stimulated insulin secretion[122]. Meanwhile, GPR120 is expressed in AT and, when activated by ω-3 fatty acids, suppresses inflammation in macrophages and promotes adipocyte differentiation. GPR120 dysfunction has been associated with obesity, hepatic steatosis, and insulin resistance. The early detrimental effects of a HFD on intestinal permeability may act as initial obesogenic triggers. Diets enriched with ω-3 fatty acids have shown modest local protective effects on the intestinal barrier. Supporting this, Rodrigues et al[123] suggest that reducing SFA intake or substituting them with ω-3 fatty acids may be effective in preserving intestinal barrier function and mitigating inflammatory responses.

FATTY ACIDS AGGRAVATE DIABETES MELLITUS IN ACUTE HLP

Diabetes of the exocrine pancreas (DEP), also referred to as type 3c diabetes mellitus (T3cDM), is a secondary form of diabetes that arises from underlying pancreatic disorders, including acute and CP. Despite its clinical distinctiveness, DEP is frequently underdiagnosed and commonly misclassified as type 2 diabetes mellitus (T2DM)[124]. Notably, HFD-induced AP contributes to the development of metabolic syndrome, a constellation of metabolic disturbances including insulin resistance, dyslipidemia, hyperglycemia, hepatic steatosis, and hypertension. This syndrome increases T2DM risk, cardiovascular disease, nonalcoholic fatty liver disease, and certain malignancies. Environmental and genetic factors, such as overnutrition, enhanced lipolysis, and adipocyte hypertrophy, drive metabolic syndrome progression, with insulin resistance as the central pathological feature. Following HFD-induced AP, patients may first develop HFD-driven diabetes, evolving into DEP. Diabetes mellitus itself exacerbates HTG and gallstone formation, both of which are risk factors for AP. Li et al[125] identified diabetes mellitus as an independent risk factor for HTG-AP, highlighting the bidirectional relationship between metabolic dysregulation and pancreatic inflammation. However, the specific subtype of diabetes following AP is often unclear, and DEP warrants specific attention in this context. In T2DM, hyperglycemia and elevated plasma FFAs, particularly SFAs such as PA, are key contributors to β-cell lipotoxicity and insulin resistance[126-128]. SFAs impair insulin secretion and promote β-cell apoptosis through oxidative stress, ER stress, and proinflammatory signaling pathways. In contrast, PUFAs, particularly ω-3 PUFAs, exhibit protective effects on pancreatic β-cells. In transgenic mfat-1 mice, which endogenously convert ω-6 to ω-3 PUFAs, increased ω-3 PUFA levels were associated with improved insulin secretion, enhanced expression of key β-cell genes (e.g., PDX-1, glucokinase, insulin-1), reduced PGE2 levels, and suppression of proinflammatory pathways such as NF-κB and ERK1/2[129]. ω-3 PUFAs also improve β-cell survival by modulating membrane lipid rafts and binding to nuclear receptors such as PPARs, GPR40 and GPR120. However, the effects of different types of UFAs are nuanced. While ω-3 PUFAs generally confer anti-inflammatory and antioxidant effects, some studies suggest that high ω-6 PUFA levels, particularly those with cis-configured double bonds, can induce significant lipid peroxidation and ferroptosis in β-cells[130]. On the other hand, long-chain SFAs primarily trigger apoptosis but can also induce ferroptosis when combined with high PUFA levels. Interestingly, MUFAs such as OA appear to mitigate oxidative stress and prevent ferroptotic β-cell death. Therefore, the dietary balance of fatty acid subtypes plays a pivotal role in β-cell health and diabetes pathogenesis. Avoiding high dietary intake of ω-6 PUFAs and excessive SFAs, while favoring MUFAs and ω-3 PUFAs, may reduce the risk of β-cell dysfunction and progression to T3cDM in individuals with AP or metabolic syndrome. Nonetheless, due to inconsistent findings in human studies, further large-scale, prospective investigations are necessary to delineate the specific mechanisms and therapeutic potential of ω-3 PUFA supplementation in diabetes prevention and management.

CONCLUSION

AP is a complex disease varying in severity and course. The different effects of HFD-induced fatty acids on AP depend on the components and substrates involved. Each stage of SAP has its own distinct mechanism. In the case of HTGP, the first step involves hypertriglyceridemia, where a high SFA diet accelerates PNLIP production, and subsequently degrades AT into triglycerides and FFAs. These FFAs directly contribute to acinar cell damage. Additionally, the acceleration of chylomicron emulsion increases pressure on the pancreatic ducts, while degradation of AT leads to necrosis and inflammation (Figure 1). The second step involves autophagy, which acts as a protective mechanism to eliminate cytokines and chemokines causing damage. However, excessive or selective blocking of autophagy promotes pro-inflammatory cytokine release. SFAs directly interact with TLR4 to stimulate an immune response, which leads to mitochondrial dysfunction, ER stress, and ROS generation, all of which promote M1 macrophage polarization (Figure 2). The third step involves increased gut permeability, which leads to elevated levels of LPS and UFAs in the bloodstream and further potentiates cytokine release. HFD-induced damage to the liver and pancreas impairs gluconeogenesis and leads to insulin resistance, contributing to acinar cell damage in the pancreas. UFAs play a critical role in AP, potentially linking obesity to poorer AP outcomes. This concept is further supported by findings from Noel et al[44], who reported elevated UFA levels in necrotic fluid collections from obese patients with AP. UFAs induce acinar cell necrosis and multisystem organ failure through pathways independent of pancreatic necrosis. These observations underscore the importance of elucidating the precise role of FAs in fatty infiltration of the pancreas, which may be key to understanding the pathophysiological mechanisms underlying SAP. In summary, increased intake of SFAs initially elevates PNLIP activity, accelerating lipolysis and fat necrosis, leading to increased FFA levels and inflammation in SAP. This process accelerates M1 macrophage polarization and subsequent acinar damage. Over time, UFAs worsen acinar cell damage and impair β-cell function in the pancreas, leading to diabetes. This cumulative effect is a consistent and damaging process. Moreover, the ratio of UFAs to SFAs is likely a valuable tool in predicting AP severity. It is essential to clearly distinguish the main roles of SFAs and UFAs in SAP development. Above all, it is becoming increasingly clear that consuming either excess SFAs or UFAs can exacerbate pancreatitis.

Figure 1 Fatty acid intake induces pancreatic lipase release to the intestine and degrades adipose to free fatty acids, stimulating pancreatitis. Saturated fatty acids combined with Toll-like receptor 4 to activate the immune response and increase oxidative stress, leading to an inflammation storm. Fatty acid alters gut permeability, damaging the gut and leading to acinar cell damage. Fatty acids significantly contribute to the progressive destruction of pancreatic β-cells, a process called lipotoxicity. UFA: Unsaturated fatty acid; TLR4: Toll-like receptor 4; FFAs: Free fatty acids; SFAs: Saturated fatty acids. Created in BioRender (Supplementary material).

Figure 2 Saturated fatty acids directly combine with Toll-like receptor 4 to stimulate nuclear factor-κB activation, which leads to increased cytokines, accelerated M1 macrophage polarization, and impaired acinar cell autophagy. UFA: Unsaturated fatty acid; TLR4: Toll-like receptor 4; FFAs: Free fatty acids; SFA: Saturated fatty acid; PPARγ: Proliferator-activated receptor gamma; TNF-α: Tumor necrosis factor α; IL: Interleukin; NF-κB: Nuclear factor-κB. Created in BioRender (Supplementary material).

ACKNOWLEDGEMENTS

We thank Justin Clark, PhD for helping with revising the manuscript.