Jiangtang Tiaozhi formula ameliorates MASLD by regulating liver ABCD2/PEX2/ATGL axis-mediated fatty acid metabolic reprogramming

Abstract

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) prevalence is rising, increasing risks of cirrhosis and hepatocellular carcinoma. The herbal formula Jiangtang Tiaozhi (JTTZF) clinically alleviates MASLD and hepatic steatosis.

Purpose: This study aimed to investigate the therapeutic effects and underlying mechanisms of JTTZF in treating MASLD via the crosstalk between peroxisomes and lipid droplets in hepatocytes.

Methods: C57BL/6 J mice on a high-fat diet (HFD) modeling MASLD received daily JTTZF or water for 12 weeks. Serum biomarkers, histology, and liver multi-omics analyses assessed metabolic status, steatosis, targets, and pathways. Oleic acid/palmitic acid-induced HepG2 cells treated with JTTZF-containing serum or ABCD2 overexpression. Mass spectrometry identified JTTZF bioavailable components. Molecular techniques evaluated effects on β-oxidation enzymes, lipid droplet proteins, peroxisomal proteins, and oxidative stress.

Results: JTTZF significantly improved glucose and lipid metabolism and hepatic steatosis in HFD-fed mice and reduced lipid droplets in liver and in HepG2 cells. DHE staining and ROS flow cytometry confirmed that JTTZF alleviated ROS levels. Multi-omics and validation using RT-PCR, western blotting, and immunohistochemistry revealed that JTTZF regulated enzymes for very long-chain fatty acid metabolism and fatty acid metabolism reprogramming in hepatocellular. Gene overexpression validated JTTZF downregulated the peroxisomal ABCD2 transporter. Mechanistically, JTTZF enhanced lipid droplet metabolism and reduced ROS via the ABCD2/PEX2/ATGL axis, ameliorating insulin resistance and MASLD.

Conclusions: This study establishes a hepatocellular fatty acid metabolic reprogramming network in MASLD. Targeting the ABCD2/PEX2/ATGL axis represents a promising therapeutic strategy, with JTTZF showing potential as a therapeutic agent for MASLD.

Keywords: ATP-binding cassette transporter; ATP-binding cassette transporter D2; Fatty acid metabolic reprogramming; Lipid droplet; Metabolic dysfunction-associated steatotic liver disease; Peroxisome.