Kaiyujiangzhuo formula alleviates glycolipid metabolic disorders by improving arginine metabolism and inhibiting the ERK-mediated PPARγ-Ser273 phosphorylation

ETHNOPHARMACOLOGICAL RELEVANCE: Kaiyujiangzhuo formula (KYJZ) is an optimized herbal formulation derived from the classical prescription "Dahuang Huanglian Xiexin decoction," recorded in the ancient Chinese monograph Shang Han Lun. For many years, KYJZ has been used to treat glycolipid metabolic disorders in China, particularly in Jilin, Changchun, and Beijing, with significant therapeutic efficacy. AIM OF THE STUDY: This study aimed to clarify the potential molecular mechanism underlying the therapeutic effect of KYJZ. MATERIALS AND METHODS: The chemical constituents of KYJZ and its absorbed components in the blood were identified using LC-MS/MS. A mouse model of glycolipid metabolic disorders was induced by feeding a high-fructose and high-fat diet (HFHFD) to evaluate the ameliorative effects of KYJZ. The mechanism of KYJZ was studied using multi-omics techniques, including transcriptomics, untargeted metabolomics, and 16S rRNA gene sequencing. RESULTS: We identified that compounds represented by neomangiferin, aloe-emodin, and ginsenoside Re may be the active constituents through which KYJZ exerts its therapeutic effects. Furthermore, we demonstrated the effectiveness of KYJZ in treating HFHFD-induced glycolipid metabolic disorders. Specifically, KYJZ reduced fasting blood glucose levels, alleviated insulin resistance, enhanced insulin sensitivity, and improved lipid profiles. Mechanistically, KYJZ reduced the hepatic activity of ERK1/2, which reduced PPARγ phosphorylation at Ser273. In addition, our comprehensive metabolomics and intestinal microbiota analysis revealed that KYJZ rectified the homeostatic imbalance of liver and intestinal arginine metabolism induced by an HFHFD. CONCLUSIONS: KYJZ exerted a beneficial effect against glycolipid metabolic disorders through a unique mechanism that inhibited hepatic PPARγ-Ser273 phosphorylation and regulated arginine metabolism homeostasis.