Exogenous acylated ghrelin promotes but un-acylated ghrelin prevents hepatic steatosis by modulating peripheral insulin resistance and hepatic oxidative and endoplasmic reticulum stress

Objectives: This study tested the effects of acylated (AG and un-acylated ghrelin (UAG) on hepatic lipid synthesis and insulin resistance (IR) from prospective to their effect on endoplasmic reticulum stress and investigated the possible underlying mechanisms. Methods: Healthy rats were divided as 4 groups (n=12/each) as control, control + AG, control + UAG, and control + AG + UAG (1:1). GA or UAG were given subcutaneously (200 ng/kg/each) for 8 weeks. Results: AG increased fasting levels of glucose and insulin resistance, increased hepatic glucose production, and impaired glucose and insulin tolerance. Besides, it increased serum levels of free fatty acids (FFAs), enhanced serum and hepatic levels of triglycerides and cholesterol, and increased lipid deposition in the livers of rats. Concomitantly, it stimulated the mRNA levels of SREBP1/2, fatty acid synthase, and protein levels of all arms of ER stress including Xbp-1, CHOP, ATF-6, and p-eIF2α, thus activating lipid synthesis and ER stress. It also reduced protein levels of p-IRS (Tyr612), p-Akt (Ser307), and increased levels of ROS, TNF-α, IL-6, and protein levels of cleaved caspase-12, p-IRS (Ser307), and p-JNK (The183/Tyr186) in rats’ livers. Administration of UAG alone or in combination with AG produced contradictory effects. However, both AG and UAG significantly increased mRNA levels of AMPK and PPARα suggesting FAs oxidation. Conclusion: AG induces hepatic steatosis and suppresses hepatic insulin signaling mainly by inducing peripheral IR that is associated with hepatic oxidative stress, inflammation, and ER stress. However, UAG alone or in combination exerts opposite effects.