2. Academic Validation
  3. Dual intestinal-hepatic modulation by phenolic acids improves metabolic-dysfunction associated steatohepatitis

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

  • Biomed Pharmacother. 2026 Feb:195:119070. doi: 10.1016/j.biopha.2026.119070.
Peter U Amadi 1,  Justice O Osuoha 2,  Joy A Amadi 3,  Esienanwan E Efiong 4,  Prince C Odika 5,  Celestine E Ekweogu 6,  Chioma Ejiofor 7,  Govind S Gill 8,  Suha J Jarad 9,  Chiamaka W Amadi 10,  Hongmei Gu 8,  Barbora de Courten 11,  Emmanuel N Agomuo 10,  Dawei Zhang 8
Affiliations

Affiliations

  • 1 Department of Pediatrics, Group on the Molecular and Cell Biology of Lipids (MCBL), University of Alberta, Edmonton, Canada; Department of Biochemistry, Imo State University, Owerri, Nigeria. Electronic address: [email protected].
  • 2 School of Chemistry, Monash University, Melbourne, Australia.
  • 3 Department of Human Nutrition and Dietetics, Imo State University, Owerri, Nigeria.
  • 4 Department of Biochemistry, Federal University of Lafia, Nigeria.
  • 5 Department of Biochemistry, Imo State University, Owerri, Nigeria; Department of Biology, St. Mary's University, Halifax, Canada.
  • 6 Department of Medical Biochemistry, Imo State University, Owerri, Nigeria.
  • 7 Department of Biochemistry, Federal University of Technology, Owerri, Nigeria.
  • 8 Department of Pediatrics, Group on the Molecular and Cell Biology of Lipids (MCBL), University of Alberta, Edmonton, Canada.
  • 9 Department of Biochemistry, Group on the MCBL, University of Alberta, Edmonton, Canada.
  • 10 Department of Biochemistry, Imo State University, Owerri, Nigeria.
  • 11 School of Health and Biomedical Sciences, RMIT University, Melbourne, Australia; Department of Medicine, School of Clinical Sciences, Monash University, Melbourne, Australia.
PMID: 41610672 DOI: 10.1016/j.biopha.2026.119070
Abstract

Background: Metabolic-dysfunction associated steatohepatitis (MASH) arises from sustained triglyceride overload of the intestine-liver axis, yet current therapies rarely coordinate intestinal lipid entry with hepatic triglyceride disposal. Here we identify a phenolic-acid fraction as a dual-compartment metabolic modulator that couples intestinal Lipase inhibition to CPT1α-PPARα-dependent hepatic β-oxidation across species.

Methods: Across species, we investigated the kinetics and metabolic actions of a phenolic fraction (PhAM) using recombinant Lipase systems, epithelial transport assays, hepatocyte models, pharmacokinetics, diet-induced Metabolic Disease paradigms, quantitative histopathology, and a 24-week randomized placebo-controlled clinical trial.

Results: PhAM selectively suppresses pancreatic and intestinal lipases non-competitively, lowering V_max with minimal K_m change, resembling some features of orlistat, but via a distinct, non-covalent mechanism. In Caco-2 monolayers and ex vivo loops, it reduces apical-to-basolateral fatty-acid flux, depletes intracellular triglycerides, and limits luminal-to-plasma lipid transfer. PhAM is orally bioavailable, with measurable plasma exposure and prolonged intestinal residence. Under high-fat feeding, it increases fecal fat loss, attenuates post-lipid-load triglyceride excursions, and lowers hepatic triglycerides without altering apoB secretion. Its triglyceride-lowering effect requires CPT1α-dependent mitochondrial import and PPARα activation, elevates β-hydroxybutyrate, and induces oxidative genes while sparing lipogenesis. In chronic MASH, PhAM reduces steatosis, ballooning, inflammation, and metabolic-dysfunction associated steatotic liver disease (MASLD) Activity Score. A 24-week clinical subgroup, defined by ultrasound and transaminase enrichment, showed dose-responsive improvements in ultrasonographic steatosis and metabolic biomarkers.

Conclusion: Collectively, these findings define PhAM as a phenolic-acid-based agent that aligns intestinal lipid restriction with hepatic oxidative unloading, offering a mechanistically coherent framework for potentially addressing steatotic liver disease-associated metabolic features.

Keywords

Beta Oxidation; Inflammation; Lipid droplets; Lipids; MASH; Phenolic acids.

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