{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T03:20:32Z","timestamp":1792120832448,"version":"4.4.0"},"reference-count":92,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,1,8]],"date-time":"2022-01-08T00:00:00Z","timestamp":1641600000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"US Department of Agriculture Hatch","award":["1014457"],"award-info":[{"award-number":["1014457"]}]},{"DOI":"10.13039\/501100004837","name":"Spanish Ministry of Science and Innovation","doi-asserted-by":"publisher","award":["RTI 2018-097504-B-I00"],"award-info":[{"award-number":["RTI 2018-097504-B-I00"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Excellence Line for University Teaching Staff within the Multiannual Agreement between the Community of Madrid and the UAM","award":["2019-2023"],"award-info":[{"award-number":["2019-2023"]}]},{"name":"FPU program of the Ministry of Universities","award":["FPU15\/04238"],"award-info":[{"award-number":["FPU15\/04238"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>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 \u00b5mol L\u22121) were used in an NAFLD cell model. Phytochemicals from the cocoa shell (50 \u00b5mol L\u22121) and an aqueous extract (CAE, 100 \u00b5g mL\u22121) enhanced ERK1\/2 phosphorylation (1.7- to 3.3-fold) and FGF21 release (1.4- to 3.4-fold) via PPAR\u03b1 activation. Oxidative stress markers were reduced though Nrf-2 regulation. Mitochondrial function (mitochondrial respiration and ATP production) was protected by the PGC-1\u03b1 pathway modulation. Cocoa shell phytochemicals reduced lipid accumulation (53\u2013115%) and fatty acid synthase activity (59\u201393%) 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, AMPK\u03b1, 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.<\/jats:p>","DOI":"10.3390\/antiox11010136","type":"journal-article","created":{"date-parts":[[2022,1,9]],"date-time":"2022-01-09T20:29:26Z","timestamp":1641760166000},"page":"136","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Phytochemicals from the Cocoa Shell Modulate Mitochondrial Function, Lipid and Glucose Metabolism in Hepatocytes via Activation of FGF21\/ERK, AKT, and mTOR Pathways"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1034-1290","authenticated-orcid":false,"given":"Miguel","family":"Rebollo-Hernanz","sequence":"first","affiliation":[{"name":"Department of Agricultural Chemistry and Food Science, Universidad Aut\u00f3noma de Madrid, 28049 Madrid, Spain"},{"name":"Institute of Food Science Research, CIAL (UAM-CSIC), 28049 Madrid, Spain"},{"name":"Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8724-6796","authenticated-orcid":false,"given":"Yolanda","family":"Aguilera","sequence":"additional","affiliation":[{"name":"Department of Agricultural Chemistry and Food Science, Universidad Aut\u00f3noma de Madrid, 28049 Madrid, Spain"},{"name":"Institute of Food Science Research, CIAL (UAM-CSIC), 28049 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9834-639X","authenticated-orcid":false,"given":"Maria A.","family":"Martin-Cabrejas","sequence":"additional","affiliation":[{"name":"Department of Agricultural Chemistry and Food Science, Universidad Aut\u00f3noma de Madrid, 28049 Madrid, Spain"},{"name":"Institute of Food Science Research, CIAL (UAM-CSIC), 28049 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7426-9035","authenticated-orcid":false,"given":"Elvira","family":"Gonzalez de Mejia","sequence":"additional","affiliation":[{"name":"Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,8]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2019, May 20). 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