Phytochemicals from the Cocoa Shell Modulate Mitochondrial Function, Lipid and Glucose Metabolism in Hepatocytes via Activation of FGF21/ERK, AKT, and mTOR Pathways.

Yolanda Aguilera,Miguel Rebollo-Hernanz,Elvira Gonzalez de Mejia,Maria A. Martin-Cabrejas

doi:10.3390/antiox11010136

Abstract

The cocoa shell is a by-product that may be revalorized as a source of bioactive compounds to prevent chronic cardiometabolic diseases. This study aimed to investigate the phytochemicals from the cocoa shell as targeted compounds for activating fibroblast growth factor 21 (FGF21) signaling and regulating non-alcoholic fatty liver disease (NAFLD)-related biomarkers linked to oxidative stress, mitochondrial function, and metabolism in hepatocytes. HepG2 cells treated with palmitic acid (PA, 500 µmol L−1) were used in an NAFLD cell model. Phytochemicals from the cocoa shell (50 µmol L−1) and an aqueous extract (CAE, 100 µg mL−1) enhanced ERK1/2 phosphorylation (1.7- to 3.3-fold) and FGF21 release (1.4- to 3.4-fold) via PPARα activation. Oxidative stress markers were reduced though Nrf-2 regulation. Mitochondrial function (mitochondrial respiration and ATP production) was protected by the PGC-1α pathway modulation. Cocoa shell phytochemicals reduced lipid accumulation (53–115%) and fatty acid synthase activity (59–93%) and prompted CPT-1 activity. Glucose uptake and glucokinase activity were enhanced, whereas glucose production and phosphoenolpyruvate carboxykinase activity were diminished. The increase in the phosphorylation of the insulin receptor, AKT, AMPKα, mTOR, and ERK1/2 conduced to the regulation of hepatic mitochondrial function and energy metabolism. For the first time, the cocoa shell phytochemicals are proved to modulate FGF21 signaling. Results demonstrate the in vitro preventive effect of the phytochemicals from the cocoa shell on NAFLD.

Highlights

Chronic diseases account for 71% of all fatalities globally, according to the WorldHealth Organization [1]
The revalorization of cocoa by-products as a source of active compounds is suggested as a strategy for preventing non-alcoholic fatty liver disease (NAFLD)
This study describes the evaluation of the phytochemicals from the cocoa shell in the activation of fibroblast growth factor 21 (FGF21) signaling, the inhibition of oxidative stress and mitochondrial dysfunction, and the modulation of lipid and glucose metabolism using HepG2 human hepatocytes

Summary

Introduction

Chronic diseases account for 71% of all fatalities globally, according to the WorldHealth Organization [1]. Dysfunctional metabolic processes in cells produce energy and redox imbalances in the body, leading to various pathophysiological metabolic conditions. Insulin resistance, type 2 diabetes, hypertension, hyperlipidemia, and metabolic syndrome are the most common chronic metabolic diseases [2]. These conditions involve the development of non-alcoholic fatty liver disease (NAFLD), a disorder characterized by excessive fat deposition in the form of triglycerides in the liver (steatosis) [3]. The current worldwide prevalence of NAFLD is estimated to be 24% [4]. These diseases could be prevented through nutrition and appropriate dietary habits [5]

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