Long-chain fatty acids - The turning point between 'mild' and 'severe' acute pancreatitis

Abstract

Acute pancreatitis (AP) is an inflammatory disease characterized by localized pancreatic injury and a systemic inflammatory response. Fatty acids (FAs), produced during the breakdown of triglycerides (TGs) in blood and peripancreatic fat, escalate local pancreatic inflammation to a systemic level by damaging pancreatic acinar cells (PACs) and triggering M1 macrophage polarization. This paper provides a comprehensive analysis of lipases' roles in the onset and progression 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 Ca²⁺ 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 inflammasome and the NF-κB pathway. Furthermore, we investigated lipid lowering therapy for AP. This review establishes a theoretical foundation for pro-inflammatory mechanisms associated with FAs in AP and facilitating drug development.

Keywords: Acinar cells; Acute pancreatitis; Inflammatory responses; Lipase; Long-chain fatty acids; Macrophages.

Fig. 1

Effect of high concentrations of OA on acinar cell function. (a) High concentrations of OA cause a continuous increase in Ca²⁺ levels, resulting in Ca²⁺ overload. (b) Continuous opening of the MPTP induced by high intracellular concentrations of Ca²⁺ 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.

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.

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.

Fig. 4

PAs mediates M1 macrophage polarization by activating the NLRP3 inflammasome. (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 inflammasome. (c) mtROS activate the NLRP3 inflammasome. (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 inflammasome. (f) PA caused Na⁺-K⁺-ATP dysfunction by affecting membrane components, and decreased K⁺ influx activated the NLRP3 inflammasome.