Hyperglycemia aggravates hepatic ischemia/reperfusion injury (IRI), but the underlying mechanism for the aggravation remains elusive. Sphingosine‐1‐phosphate (S1P) and sphingosine‐1‐phosphate receptors (S1PRs) have been implicated in metabolic and inflammatory diseases. Here, we discuss whether and how S1P/S1PRs are involved in hyperglycemia‐related liver IRI. For our in vivo experiment, we enrolled diabetic patients with benign hepatic disease who had liver resection, and we used streptozotocin (STZ)–induced hyperglycemic mice or normal mice to establish a liver IRI model. In vitro bone marrow–derived macrophages (BMDMs) were differentiated in high‐glucose (HG; 30 mM) or low‐glucose (LG; 5 mM) conditions for 7 days. The expression of S1P/S1PRs was analyzed in the liver and BMDMs. We investigated the functional and molecular mechanisms by which S1P/S1PRs may influence hyperglycemia‐related liver IRI. S1P levels were higher in liver tissues from patients with diabetes mellitus and mice with STZ‐induced diabetes. S1PR3, but not S1PR1 or S1PR2, was activated in liver tissues and Kupffer cells under hyperglycemic conditions. The S1PR3 antagonist CAY10444 attenuated hyperglycemia‐related liver IRI based on hepatic biochemistry, histology, and inflammatory responses. Diabetic livers expressed higher levels of M1 markers but lower levels of M2 markers at baseline and after ischemia/reperfusion. Dual‐immunofluorescence staining showed that hyperglycemia promoted M1 (CD68/CD86) differentiation and inhibited M2 (CD68/CD206) differentiation. Importantly, CAY10444 reversed hyperglycemia‐modulated M1/M2 polarization. HG concentrations in vitro also triggered S1P/S1PR3 signaling, promoted M1 polarization, inhibited M2 polarization, and enhanced inflammatory responses compared with LG concentrations in BMDMs. In contrast, S1PR3 knockdown significantly retrieved hyperglycemia‐modulated M1/M2 polarization and attenuated inflammation. In conclusion, our study reveals that hyperglycemia specifically triggers S1P/S1PR3 signaling and exacerbates liver IRI by facilitating M1 polarization and inhibiting M2 polarization, which may represent an effective therapeutic strategy for liver IRI in diabetes.
Background: Our previous study demonstrated that preoperative short-term fasting attenuates mice hepatic ischemia/reperfusion injury (IRI), which greatly piqued our interest in verifying if fasting produces similar protective effects in patients undergoing hepatectomy. Methods: Eighty patients with liver tumors were randomized into control (Ctrl, n=40, preoperative fasting for 6 h) or fasting group (Fasting, n=40, preoperative fasting for 24 h). Serum was collected at pre-operation (Pre-Op), post-operation 1 day (POD-1), post-operation 3 days (POD-3), and post-operation 7 days (POD-7). Liver tissue was removed from the resected specimen. Results: Sixty-three patients were eventually enrolled, with 33 in Ctrl and 30 in Fasting group. Our data showed that 24 h fasting effectively attenuated elevated sALT and sAST levels after operation (P<0.05), but serum total bilirubin was significantly lower at only POD-3 (P<0.05); and serum albumin was not markedly different in either of the groups. Interestingly, 24 h fasting partially attenuates expression of pro-inflammatory cytokine (TNF-α) and improves oxidative stress (MDA and SOD). Our data further showed short-term fasting triggered Nrf2 signaling pathway. Conclusions: This study demonstrates preoperative short-term fasting effectively improves clinical outcomes and markedly attenuates inflammatory responses and oxidative stress in patients undergoing hepatectomy, and Nrf2 signaling pathway may play a key role in fasting against inflammatory responses and oxidant stress.
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