Background:Non-alcoholic liver disease is of increased concern and contributing to economic burdens not only in developing countries but in developed countries as well.Identifying the biomarker of early diagnosis and early intervention approaches for non-alcoholic liver disease is unmet and required further investigation.Although the alpha-ketoglutarate(α-KG)is recently proposed to be a potential biomarker in differentiating patients with obesity from those with non-alcoholic liver disease,how α-ketoglutatate is involved in the fatty liver progression is not clear. Methods:A high-fat diet(HFD)feeding animal model,liver functional assays,and molecular approaches were adopted to clarify the impact of α-KG in fatty liver progression. Results:In the current study,it was found that dietary α-KG would inhibit weight gain in male and female mice fed with a normal chew or HFD.HFD feeding caused fatty liver in male mice,but α-KG treatment could substantially inhibit hepatic steatosis progression.Biochemical studies revealed the possible linkage of α-KG protective functions to lipid metabolism.Further analysis identified the important role of peroxisome proliferator-activated receptors in beneficial α-KG-mediated effects on fatty liver progression. Conclusions:The current study demonstrates the therapeutic potential of α-KG and how it may be used,via dietary supplementation,as a preventive intervention for non-alcoholic liver disease in obese patients.