Dual intestinal-hepatic modulation by phenolic acids improves metabolic-dysfunction associated steatohepatitis

Area of Science:

• Biochemistry
• Hepatology
• Pharmacology

Background:

• Metabolic dysfunction-associated steatohepatitis (MASH) is driven by excess intestinal lipid absorption and impaired hepatic triglyceride disposal.
• Current MASH therapies lack coordinated strategies for intestinal lipid management and hepatic fat metabolism.
• A phenolic-acid fraction (PhAM) is identified as a potential dual-compartment metabolic modulator.

Purpose of the Study:

• To investigate the mechanisms and efficacy of a phenolic-acid fraction (PhAM) in modulating lipid metabolism.
• To assess PhAM's ability to inhibit intestinal lipases and enhance hepatic fatty acid oxidation.
• To evaluate PhAM's therapeutic potential in preclinical models and a clinical trial for MASH/MASLD.

Main Methods:

• Investigated PhAM kinetics and actions using in vitro lipase systems, epithelial transport assays, and hepatocyte models.
• Conducted pharmacokinetic studies and evaluated PhAM in diet-induced metabolic disease models.
• Performed quantitative histopathology and a 24-week randomized, placebo-controlled clinical trial in patients with MASH/MASLD.

Main Results:

• PhAM non-competitively inhibits pancreatic and intestinal lipases, reducing fatty acid absorption and intracellular triglycerides.
• Oral administration of PhAM leads to increased fecal fat excretion and reduced post-lipid load triglyceride levels.
• PhAM enhances hepatic fatty acid oxidation via CPT1α-PPARα activation, reducing liver steatosis and improving MASH/MASLD Activity Score.
• Clinical trial subgroup showed dose-responsive improvements in ultrasonographic steatosis and metabolic biomarkers.

Conclusions:

• PhAM acts as a phenolic-acid-based agent that synchronizes intestinal lipid restriction with hepatic oxidative unloading.
• This dual-action mechanism provides a coherent framework for addressing metabolic features associated with steatotic liver disease.
• PhAM demonstrates potential as a novel therapeutic agent for MASH/MASLD.