Exogenous administration of unacylated ghrelin attenuates hepatic steatosis in high-fat diet-fed rats by modulating glucose homeostasis, lipogenesis, oxidative stress, and endoplasmic reticulum stress

Low levels of unacylated ghrelin (UAG) and a higher ratio of acylated ghrelin (AG)/UAG in obesity are associated with non-alcoholic fatty liver disease (NAFLD). This study tested the potential protective effect of increased circulatory levels of UAG by exogenous UAG administration on hepatic steatosis in high-fat diet (HFD)-fed rats and investigated some possible mechanisms. Rats were divided (n = 6/group) as low fat diet (LFD), LFD + UAG (200 mg/kg), HFD, HFD + UAG (50, 100, or 200 mg/kg). Treatments were given for 8 weeks. Increasing the dose of UAG increased circulatory levels of UAG and normalized the ratio of AG/UAG at the dose of 200 mg/kg. With no change in insulin levels, and in a dose-dependent manner, treatment with UAG to HFD rats attenuated the gain in food intake, body weights, and liver weights, lowered fasting glucose levels, prevented hepatic cyto-plasmic vacuolization, and reduced serum and hepatic levels of cholesterol, triglycerides, and free fatty acids. They also progressively reduced levels of reactive oxygen species, lipid peroxides, tumor necrosis factor-alpha, and interleukin-6, as well as mRNA levels of Bax and caspase-3 but increased levels of glutathione and superoxide dismutase and mRNA levels of Bcl2. In concomitant, UAG, in a dose-response manner, significantly reduced hepatic mRNA levels of SREBP1, SREBP2, ATF-6, IRE-1, and eIF-2 alpha but increased those of PPAR alpha. In conclusion, reducing the circulatory ratio of AG/UAG ratio by exogenous administration of UAG attenuates HFD-induced hepatic steatosis by suppressing lipogenesis, stimulating FAs oxidation, preventing oxidative stress, inflamma-tion, ER stress, and apoptosis.