Clinical investigation of lipopolysaccharide in the persistence of metabolic syndrome (MS) through the activation of GRP78-IRE1α-ASK1 signaling pathway

Objective: Endoplasmic reticulum stress (ERS) might play a pivotal role in the persistence of metabolic syndrome (MS). Lipopolysaccharide (LPS) derived from various gram-negative bacteria could result in the ERS. Therefore, we aimed to investigate the association between LPS and ERS in MS.

Method: We enrolled 86 patients with MS and 42 healthy people aged 35-65 years. Body weight, waist circumference, blood pressure were measured. LPS, LBP and inflammation factors, fasting plasma glucose (FPG), insulin, total cholesterol (TC), triglyceride, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), free fatty acid (FFA) were analyzed in blood plasma of patient's cohort. Body mass index (BMI) and HOMA-IR were calculated. The mRNA and protein expression of ERS GRP78, IRE1α, ASK1 and IKKβ, JNK1 were measured in blood plasma of patient's cohort by RT-PCR and Elisa. MS was defined by the updated National Cholesterol Education Program Adult Treatment Panel III criterion for Asian Americans.

Results: BMI, waist circumference, blood pressure, FPG, insulin, HOMA-IR, TC, triglyceride, HDL-C, LDL-C, FFA and LPS, LBP, TNF-α, CRP, IL-1, IL-6, MCP-1 were significantly higher in patients with MS than healthy people (P < 0.001). The correlation analysis suggested that LPS were associated with TNF-α, IL-1, IL-6, MCP-1, LBP, FFA, HOMA-IR potently (P < 0.05). The marker gene and protein expressions of ERS (GRP78, IRE1α, ASK1, IKKβ and JNK) were significantly overexpressed in patients with MS and were positive correlation with LPS (P < 0.05).

Conclusion: LPS may play an important role in mediating chronic low-grade inflammation by activating the ERS GRP78-IRE1α-ASK1 signaling pathway, contributing to the persistence of MS.