Dataset Information

Zhaqu Compound Improves Glucose and Lipid Metabolism in T2DM with MASLD by Modulating Gut Microbiota and PPARγ

ABSTRACT:

Type 2 diabetes mellitus (T2DM) with metabolic syndrome-associated steatohepatitis (MASLD) is a complex metabolic comorbidity characterized by hyperglycemia, pancreatic β-cell dysfunction, and hepatic lipid metabolism disorders, in which gut microbiota dysbiosis and abnormal PPARγ signaling play pivotal roles. Zhaqu Compound (ZQC), a traditional Chinese herbal formula, has demonstrated clinical efficacy in improving glucose and lipid metabolism, though its mechanisms remain unclear. In this study, db/db mice with T2DM-MASLD were treated for 12 weeks with ZQC, metformin, or saline, and metabolic outcomes were evaluated via blood glucose, lipid profiles, hepatic lipid accumulation, hepatocyte ultrastructure, gut microbiota (16S rRNA), non-targeted metabolomics, and liver transcriptomics. In high-glucose + palmitate-induced HepG2 cells, ZQC-containing serum and the PPARγ agonist GW1929 were applied, and Western blot was used to assess key gluconeogenic and lipogenic proteins. LC-MS, network pharmacology, and molecular docking identified major ZQC components and their potential interactions with PPARγ. ZQC improved glycemia, insulin resistance, and lipid profiles, and alleviated hepatic steatosis. It increased beneficial gut bacteria (Bacteroidetes, Lactobacillales) and partially restored Lachnospiraceae and Muribaculaceae, modulated amino acid metabolism and AGE-RAGE/mTOR pathways, and activated hepatic PPARγ signaling while regulating fatty acid and arachidonic acid metabolism. In HepG2 cells, ZQC reduced lipid droplet accumulation, lowered triglyceride and total cholesterol levels, enhanced glucose uptake, downregulated key gluconeogenic and lipogenic proteins, and moderately decreased PPARγ and its downstream transporters (CD36, FABP4). N-phenethylhexadecanamide, palmitic acid, and isoflavone likely mediate these effects. Collectively, ZQC improves glucose and lipid metabolism in T2DM with MASLD by modulating gut microbiota, moderately regulating PPARγ signaling, and enhancing β-cell function, providing mechanistic insight into its therapeutic potential.

INSTRUMENT(S): Gas Chromatography MS - positive

PROVIDER: MTBLS13933 | MetaboLights | 2026-02-25

REPOSITORIES: MetaboLights

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	a_MTBLS13933_GC-MS_positive__metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS13933_GC-MS_positive__metabolite_profiling_v2_maf.tsv	Tabular
	s_MTBLS13933.txt	Txt

Items per page:

1 - 4 of 4

Similar Datasets

Project description:Fat accumulation, de novo lipogenesis, and glycolysis are key contributors to hepatocyte reprogramming and the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). The molecular mechanisms affected by steatosis and inflammation in the obese states remain unknown. Here we report that obesity leads to dysregulated expression of protein-tyrosine phosphatases (PTPs) in the liver. Protein Tyrosine Phosphatase Receptor Kappa (PTPRK) was increased in hepatocytes by steatosis and inflammation in humans and mice, and positively correlates with PPARγ-induced lipogenic signalling. Mechanistically, PTPRK-PPARγ upregulation by fat accumulation is dependent upon Notch signalling in mouse primary hepatocytes. PTPRK knockout mice have reduced fat accumulation in adipose tissue and liver after exposure to an obesogenic diet. Phosphoproteomic analysis in isolated hepatocytes and hepatic metabolomics identified specific phosphotyrosine residues in fructose-1,6 bisphosphatase-1 and glycolysis regulation as targets of PTPRK. These changes in glycolysis and de novo lipogenesis revealed PTPRK-dependent metabolic reprogramming in hepatocytes. Moreover, hepatoma cell lines showed reduced colony-forming ability after PTPRK silencing in vitro, and PTPRK knockout mice developed smaller tumours after diethylnitrosamine-induced hepatocarcinogenesis in vivo. Computational modelling identified potential PTPRK inhibitors, which selectively reduced PTPRK activity. The compounds decreased glycolytic rates in hepatoma cell lines, PPARγ expression in primary hepatocytes and steatosis in obese mice. In conclusion, our study defines a novel mechanism for the development of MASLD, revealing a key role of PTPRK on hepatic glycolysis regulation with implications in lipid metabolism, and liver tumour development. We propose PTPRK as a potential target for metabolic liver dysfunction, and the identified inhibitors may represent promising candidates for therapy in obesity-associated liver diseases.

Project description:Metabolic dysfunction within the liver is a major cause of human disease worldwide. Fat accumulation, de novo lipogenesis, and glycolysis are key drivers of hepatocyte reprogramming and the consequent metabolic dysfunction-associated steatotic liver disease (MASLD). The underpinning molecular mechanisms affected by steatosis and inflammation in the obese states remain unknown. Here we report that obesity leads to dysregulated expression of protein-tyrosine phosphatases (PTPs) in the liver. Protein Tyrosine Phosphatase Receptor Kappa (PTPRK) expression was increased in hepatocytes during steatosis and inflammation in humans and mice, and positively correlates with PPARγ-induced lipogenic signalling. Supporting this, PTPRK knockout mice displayed reduced fat accumulation in adipose tissue and liver after exposure to an obesogenic diet. Phosphoproteomic analysis in primary hepatocytes and hepatic metabolomics identified specific phosphotyrosine residues in fructose-1,6 bisphosphatase-1 and glycolysis regulation as targets of PTPRK. The changes in glycolysis and de novo lipogenesis revealed PTPRK was a driving force for metabolic reprogramming in hepatocytes. Moreover, hepatoma cell lines showed reduced colony-forming ability after PTPRK silencing in vitro, and PTPRK knockout mice developed smaller tumours after diethylnitrosamine-induced hepatocarcinogenesis in vivo. Through computational modelling, we identified selective PTPRK inhibitors. These compounds decreased glycolytic rates in hepatoma cell lines, PPARγ expression in primary hepatocytes and steatosis in obese mice. In conclusion, our study defines a novel mechanism for the development of MASLD, revealing a key role of PTPRK on hepatic glycolysis regulation with implications in lipid metabolism, and liver tumour development. We propose PTPRK as a potential target for metabolic liver dysfunction, and the identified inhibitors may represent promising candidates for therapy in obesity-associated liver diseases.

Dataset Information

Zhaqu Compound Improves Glucose and Lipid Metabolism in T2DM with MASLD by Modulating Gut Microbiota and PPARγ

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets