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.

Some diseases related to lipid metabolism increase yearly in cultured fish, and the farnesoid X receptor (FXR) is a nuclear protein that plays a key role in inflammatory responses and lipid metabolism. However, the roles of FXR in hybrid grouper (Epinephelus fuscoguttatus♀ × E. lanceolatus♂) remain poorly understood. The main objective of this study was to explore the roles of hepatic FXR in triggering the immune response and the potential functions of FXR in regulating the lipid metabolism. In the present study, the full-length sequence of fxr from hybrid grouper was cloned and characterized for the first time. Upon the Vibrio parahaemolyticus stimulation, the transcriptional level of fxr was rapidly elevated in the head kidney tissue in the early stage of infection. In vivo and vitro, activation of FXR by obeticholic acid (OA) significantly increased the concentrations and mRNA levels of hepatic inflammatory cytokines. These effects were inversed when FXR was inhibited by guggulsterone (GU). Moreover, the activation of FXR to suppress the PI₃K/AKT/mTOR signaling pathway improves hepatic lipid metabolism and reduces hepatic lipid accumulation in vivo and vitro. In addition, the inhibition of FXR activated the PI₃K/AKT/mTOR pathway, decreased the lipolysis and increased the lipogenesis, and subsequently increased the lipid accumulation in fish. These results revealed the positive roles of FXR in triggering immune responses and improving lipid metabolism and accumulation in hybrid grouper.

The pathophysiology of psoriasis is complex and has not been completely elucidated. Better understanding of the pathogenesis may contribute to further improvement of our therapeutic strategies controlling psoriasis. Emerging evidence points to a causative relationship between altered activity of peroxisome proliferator-activated receptor γ (PPARγ) and psoriasis. The present review focuses on deeper understanding of the possible role of PPARγ in the pathogenesis of psoriasis and the potential of PPARγ agonist to improve the treatment of psoriasis. PPARγ is decreased in psoriasis. PPARγ possibly has effects on the multiple aspects of the pathogenesis of psoriasis, including abnormal lipid metabolism, insulin resistance, immune cells, pro-inflammatory cytokines, keratinocytes, angiogenesis, oxidative stress, microRNAs and nuclear factor kappa B. As defective activation of PPARγ is involved in psoriasis development, PPARγ agonists may be promising agents for treatment of psoriasis. Pioglitazone appears an effective and safe option in the treatment of patients with psoriasis, but there are still concerns about its potential side effects. Research effort has recently been undertaken to explore the PPARγ-activating potential of natural products. Among them some have been studied clinically or preclinically for treatment of psoriasis with promising results.

Phosphatidylinositol 3‑kinase (PI3K)/protein kinase B (Akt) has been indicated to serve an important role in the pathogenesis of inflammatory diseases. It was previously demonstrated that the PI3K/Akt inhibitor wortmannin alleviated the severity of inflammation and improved the survival rate in rats with induced severe acute pancreatitis (SAP), which indicates that PI3K/Akt may serve a role in the pathogenesis of acute pancreatitis. To date, the mechanism by which PI3K/Akt regulates inflammation has not been elucidated. In the present study, it was hypothesized that PI3K/Akt may be invovled in SAP inflammation via regulation of the Toll‑like receptor 4 (TLR4) signaling pathway. Rats with SAP were treated with the PI3K/Akt agonist insulin‑like growth factor (IGF)‑1, which alleviated the severity of inflammation in a dose‑dependent manner. Furthermore, to better understand the role of PI3K/Akt in inflammation, RAW264.7 murine macrophages were stimulated with IGF‑1 and wortmannin alone or together before the induction of inflammation by treatment with lipopolysaccharide (LPS). The results indicated that LPS stimulated overexpression of TLR4, myeloid differentiation primary response gene 88 (MyD88), PI3K, Akt, p38MAPK and NF‑κBp65 mRNA, and increased the levels of tumor necrosis factor (TNF)‑α and interleukin (IL)‑6 in RAW264.7 cells compared with the control group. The levels of all detected factors were increased by stimulation with IGF‑1, whereas these levels were decreased following treatment with wortmannin alone, and the effect of IGF‑1 was abolished by wortmannin in RAW264.7 cells. In vivo studies indicated that IGF‑1 produced the same anti‑inflammatory effect as wortmannin and that expression of TLR4, p38MAPK and NF‑κBp65 decreased following treatment with IGF‑1. These findings indicate that PI3K/Akt may take part in the progression of SAP by regulating the TLR4 signaling pathway and that IGF‑1 can inhibit inflammation in SAP rats.

Acute pancreatitis (AP) is an inflammatory disorder of the exocrine pancreas frequently associated with metabolic causes, contributing factors, or consequences, including hypertriglyceridemia, obesity, and disorders of intermediary metabolism, respectively. To date, there is no specific therapy for this disease. Future optimal therapy should correct both inflammatory and metabolic components of the disease. Peroxisome proliferator-activated receptors (PPARs) are lipid-sensing nuclear receptors that control inflammatory and metabolic pathways via ligand-dependent and ligand-independent mechanisms. There are 3 known subtypes, PPAR-α, PPAR-β/δ, and PPAR-γ, which are differentially expressed in various tissues. The PPARs interact closely with other transcription factors such as nuclear factor κB and signal tranducers and activators of transcription that have pivotal roles in the pathobiology of AP. In this comprehensive review, we summarize the role of PPARs in AP, highlighting important in vitro and in vivo experimental findings. Finally, we propose future research directions as well as potential translational use of PPAR agonists in the treatment of AP.

Type 2 diabetes is a complex disease with multiple defects, which generally requires a combination of several pharmacological approaches to reach glucose control targets. A unique fixed-dose combination combines a thiazolidinedione (pioglitazone) and a dipeptidyl peptidase-4 inhibitor (alogliptin).

An extensive literature search was performed to analyze the pharmacokinetics of pioglitazone and alogliptin when used separately and in combination as well as to summarize clinical and toxicological considerations about the combined therapy.

Pioglitazone, a potent insulin sensitizer, and alogliptin, an incretin-based agent that potentiates post-meal insulin secretion and reduces glucagon secretion, have complementary mechanisms of action. The clinical efficacy of a combined therapy is superior to any single therapy in patients treated with diet or with metformin (with or without sulphonylurea). These two drugs can be administered once daily, with or without a meal. No clinically relevant pharmacokinetic interactions between the two agents have been described and the fixed-dose combination has shown bioequivalence with alogliptin and pioglitazone given separately. Combining alogliptin with pioglitazone does not alter the safety profile of each compound. Weight gain observed with pioglitazone may be limited with the addition of alogliptin. The concern of an increased risk of heart failure remains to be better investigated.

The question whether antidiabetes drugs can cause acute pancreatitis dates back to the 1970s. Recently, old concerns have re-emerged following claims that use of incretins, a new class of drugs for type 2 diabetes, might increase the relative risk of acute pancreatitis up to 30-fold. Given that diabetes is per se a potent risk factor for acute pancreatitis and that drug-related acute pancreatitis is rare and difficult to diagnose, we searched the medical databases for information linking acute pancreatitis and type 2 diabetes drugs. Among the biguanides, both phenformin and metformin (the latter in patients with renal insufficiency) have been cited in case reports as a potential cause of acute pancreatitis. Sulphonylureas, as both entire class and single compound (glibenclamide), have also been found in cohort studies to increase its risk. No direct link was found between pancreatic damage and therapy with metaglinide, acarbose, pramlintide or SGLT-2 inhibitors. In animal models, thiazolinediones have demonstrated proprieties to attenuate pancreatic damage, opening perspectives for their use in treating acute pancreatitis in humans. Several case reports and the US Food and Drug Administration pharmacovigilance database indicate an association between acute pancreatitis and incretins, dipeptidyl peptidase-4 (DPP-4) inhibitors, and GLP-1 receptor agonists. To date, however, a clear-cut odds ratio for this association has been reported in only one of eight pharmacoepidemiological studies. Finally, none of the intervention trials investigating these compounds, including two large randomized controlled trials with cardiovascular endpoints, confirmed the purportedly increased risk of acute pancreatitis with incretin use.

To investigate the effects and mechanisms of peroxisome proliferator-activated receptor-γ (PPAR-γ) activation on the induction of apoptosis in rats with acute pancreatitis.

Severe acute pancreatitis (SAP) and mild acute pancreatitis (MAP) were induced and pre-treated with pioglitazone, which is a ligand of PPAR-γ. The expression of inflammatory factors (TNF-α and IL6) of the pancreas was detected by ELISA. The apoptosis in pancreas were detected by TUNEL assay and the activity of caspase 3 was determined. Phosphorylation of p65 in pancreas of SAP or MAP was determined by western-blot.

Expression levels of PPAR-γ proteins were elevated in the pancreases of SAP or MAP rats pre-injected with pioglitazone intraperitoneally. Downregulation of the expression TNF-α and IL6 and relief of pathological changes in the pancreas suggested that pioglitazone had protective effects on acute panceatitis. In pioglitazone pre-treated groups, a TUNEL assay indicated a high level of apoptosis in SAP but little apoptosis in MAP, showing pioglitazone could promote taurocholate-induced apoptosis but inhibit ceruleininduced apoptosis in pancraeatic aniniar cells. Furthermore, caspase 3 activity was high in SAP but low in MAP, implying that the apoptotic mechanism in pancreatic acinar cells of AP rats was correlated with caspase 3 activity. Phosphorylation of p65 was reduced in SAP or MAP group pretreated with pioglitazone, indicating that pioglitazone reduced the inflammation reaction by inhibiting the activation of the NF-κB.

These results indicated that activation of PPAR-γ induced apoptosis in pancreatic acinar cells of SAP rats but inhibited apoptosis in pancraeatic acinar cells of MAP rats, which demonstrated that PPAR-γ may be an efficiently therapeutic target in pancreatic inflammation.

We investigated whether pancreatitis-associated ascitic fluid (PAAF) could induce the expression of tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) in THP-1 cells and the mechanism(s) involved.

THP-1 cells were divided into control and PAAF groups. The PAAF group was incubated with different final concentrations of PAAF, whereas the control group was incubated with culture medium. Effects and mechanisms were determined by measuring the levels of TNF-α and IL-6 mRNA expression; phospho-p38-MAPK, nuclear factor κB, peroxisome proliferator-activated receptor γ activation; and the effect on the inhibitory activity of SB203580 and BAY-117082.

In response to PAAF, overexpression of TNF-α and IL-6 mRNA was found in THP-1 cells compared with those of the corresponding control (P < 0.05), and in a dose-dependent manner. The levels of phospho-p38 and nuclear factor κB p65 were also increased in different PAAF groups, whereas low expression of peroxisome proliferator-activated receptor γ was found compared with the control group (P < 0.05). Furthermore, we presented that the inflammatory response could be partly alleviated by inhibitors SB203580 or BAY-117082, whereas it was markedly inhibited by the simultaneous treatment of 2 inhibitors.

Pancreatitis-associated ascitic fluid up-regulated proinflammatory cytokines by interfering with proinflammatory and anti-inflammatory signaling pathways, thus exacerbating activation in acute pancreatitis.