# Chronic high‐fat diet induces multi‐organ dysfunction and metabolic homeostasis disruption in Macaca fascicularis

## TL;DR

A high-fat diet in macaques over 18 months caused metabolic disorders like fatty liver disease, diabetes, and heart issues, with specific proteins linked to these conditions.

## Contribution

The study establishes a translational non-human primate model of metabolic dysfunction and identifies novel biomarkers for MASH, diabetes, and cardiac hypertrophy.

## Key findings

- MASH was confirmed in 57.14% of macaques after 18 months of HFD.
- Proteomic analysis identified BAAT as a MASH hallmark protein inversely correlated with fibrosis.
- Myocardial hypertrophy was associated with downregulation of SRC, MAPK14, EMD, and ITGB1.

## Abstract

The aim of the study was to develop a non‐human primate model of metabolic dysfunction in Macaca fascicularis using chronic high‐fat diet (HFD) to mimic clinical disease progression.

Thirty‐five male macaques aged 10–15 years underwent an 18‐month HFD intervention. Physiological parameters (BMI, BP, hematology), liver fat fraction (evaluated by ultrasound/MRI), cardiac function (assessed by echocardiography), and histopathology (using liver biopsy) were measured before and after the intervention. Serum proteomics with KEGG/STRING analyses identified molecular mechanisms.

Within 6 months, HFD induced dyslipidemia (elevated TG, TCHO, HDL‐C, LDL‐C). After 18 months, metabolic dysfunction‐associated steatohepatitis (MASH) was confirmed by histopathology in 57.14% (16/28) of macaques, diabetes (elevated FPG/HbA1c) in 17.86% (5/28), and myocardial hypertrophy (elevated LVMass/LAD) in 46.43% (13/28). Proteomics identified Bile acid‐CoA: amino acid N‐acyltransferase (BAAT) as a MASH hallmark protein, the level of which was inversely correlated with the degree of fibrosis. For diabetes, citrate synthase (CS) and malate dehydrogenase 1 (MDH1) impaired glucose oxidation via the TCA cycle, while hexose‐6‐phosphate dehydrogenase (H6PD) disrupted gluconeogenesis. Myocardial hypertrophy was associated with the downregulation of SRC proto‐oncogene, non‐receptor tyrosine kinase (SRC), mitogen‐activated protein kinase 14 (MAPK14), emerin (EMD), and integrin subunit beta 1 (ITGB1).

An 18‐month HFD successfully established a translational M. fascicularis model replicating key metabolic disorders (MASH, diabetes, cardiac hypertrophy). BAAT, CS/MDH1/H6PD, and SRC/MAPK14/EMD/ITGB1 were identified as mechanistic biomarkers for these conditions.

An 18‐month HFD successfully established a translational Macaca fascicularis model replicating key metabolic disorders (MASH, diabetes, cardiac hypertrophy). MASH was determined by liver biopsy histology, the presence steatosis, inflammatory infiltration, hepatocytic ballooning, and fibrosis were considered as MASH; diabetes was diagnosed according to levels of fasting blood glucose and glycated hemoglobin (HbA1c), it defined by fasting blood glucose ≥7.0 mmol/L and glycated hemoglobin (HbA1c) ≥6.5%; and myocardial hypertrophy was identified based on increased (≥20%) Left Ventricular Mass (LVMass) measured by echocardiography. Base on serum proteomics, BAAT, CS/MDH1/H6PD, and SRC/MAPK14/EMD/ITGB1 were identified as mechanistic biomarkers for these metabolic disorders.