Lycium barbarum Polysaccharide Fraction Ameliorates Palmitate-Induced Insulin Signaling Impairment in HepG2 Cells: Transcriptomic Evidence for the Potential Association with the DAG-PtdOH Metabolic Axis and the AMPK/ULK1 Autophagy Pathway

LBP (300 μg/mL) partially restores glucose consumption and glycogen content. Transcriptomic analysis suggests that these protective effects are potentially associated with the upregulation of glycerophospholipid–DAG-PtdOH signaling and ULK1-dependent autophagy. These preliminary findings provide transcriptional insights into a potential dual botanical mechanism, though further protein-level validation is required. Objective: The objective of this study was to investigate the ameliorative effects of LBP on palmitic acid (PA)-induced cellular dysfunction (or insulin signaling impairment) in HepG2 cells and the potential molecular mechanisms. Methods: LBP was extracted by hot water extraction–ethanol precipitation and characterized by the phenol-sulfuric acid method, Fourier-transform infrared spectroscopy (FT-IR) and nuclear magnetic resonance (NMR) spectroscopy for content determination and structural characterization. The CCK-8 assay was used to determine the safe concentrations of PA and LBP. Glucose consumption and glycogen content were measured by the glucose oxidase method. Transcriptome sequencing combined with GO and KEGG enrichment analyses was performed to screen key pathways and differentially expressed genes (DEGs). RT-qPCR was used to validate the mRNA expression of DGKA, LPIN1, and ULK1. Results: LBP was identified as a pyranose-type acidic heteropolysaccharide containing uronic acid. Compared with the control group, PA treatment significantly decreased glucose consumption and glycogen content (p < 0.05), both of which were significantly ameliorated by 300 μg/mL LBP intervention (p < 0.05). Transcriptome sequencing identified 1752 DEGs, and KEGG enrichment analysis indicated that LBP treatment was associated with transcriptional changes in glycerophospholipid metabolism, AMPK signaling, and autophagy pathways. RT-qPCR further showed that LBP significantly upregulated the mRNA expression of DGKA, LPIN1, and ULK1 (p < 0.05). However, these mechanistic insights are limited to the transcriptional level and require further protein-level validation. Conclusions: LBP exhibited protective effects against PA-induced insulin signaling impairment in HepG2 cells, which were potentially associated with the transcriptional regulation of the DAG-PtdOH metabolic axis and AMPK/ULK1 pathway-related genes. However, these mechanistic inferences are speculative and require validation via protein and inhibitor experiments.