An Herbal Formula Alleviates Lipotoxicity and Glucotoxicity by Regulating AMPK/SIRT1 in Zucker Diabetic Fatty Rats

INTRODUCTION: This study aimed to investigate the effects of a Chinese herbal formula on the regulation of hepatic lipid metabolism in an inbred rat model of diabetes. METHODS: ZDF (fa/fa) rats were administered the herbal formula for six weeks following a fiveweek feed of a high-fat diet. Blood glucose was monitored weekly. An oral glucose tolerance test (OGTT) and magnetic resonance imaging (MRI) were performed before sacrifice. The profiles of lipid and glucose in serum were determined, and the transcriptomic analysis was conducted. AMPK signaling was detected by PCR, western blot, and immunohistochemistry. RESULTS: The herbal formula improved glucose tolerance and insulin sensitivity, reduced plasma glucose and lipid, alleviated pathological changes, and decreased hepatic lipid accumulation. Transcriptomic analysis predicted that AMPK signaling was a key pathway through which the herbal formula regulated hepatic lipid metabolism. The herbal formula upregulated the expressions of AMPKα, SIRT1, and PGC1α in the liver of ZDF rats. DISCUSSION: The obese ZDF (fa/fa) rat, characterized by hyperglycemia, hyperlipemia, insulin resistance, and hepatic steatosis, closely mimics human T2DM. AMPK signaling plays a significant role in hepatic lipid metabolism, especially in the process of gluconeogenesis and glycogen synthesis. The herbal formula Qi Hua Tong Tiao is derived from ancient Chinese medical books in light of the Qi transformation theory. It alleviated lipotoxicity, glucotoxicity, and regulated hepatic lipid metabolism by up-regulating AMPK signaling. This study provided experimental evidence supporting the herbal formula as a promising alternative therapy for lipid disorders in diabetes. CONCLUSION: The Chinese herbal formula alleviated lipotoxicity and glucotoxicity by regulating AMPK/SIRT1 in the liver of ZDF rats.