Impact of the Co-Administration of N-3 Fatty Acids and Olive Oil Components in Preclinical Nonalcoholic Fatty Liver Disease Models: A Mechanistic View

Abstract

Nonalcoholic fatty liver disease (NAFLD) is present in approximately 25% of the population worldwide. It is characterized by the accumulation of triacylglycerol in the liver, which can progress to steatohepatitis with different degrees of fibrosis, stages that lack approved pharmacological therapies and represent an indication for liver transplantation with consistently increasing frequency. In view that hepatic steatosis is a reversible condition, effective strategies preventing disease progression were addressed using combinations of natural products in the preclinical high-fat diet (HFD) protocol (60% of fat for 12 weeks). Among them, eicosapentaenoic acid (C20:5n-3, EPA) and docosahexaenoic acid (C22:5n-3, DHA), DHA and extra virgin olive oil (EVOO), or EPA plus hydroxytyrosol (HT) attained 66% to 83% diminution in HFD-induced steatosis, with the concomitant inhibition of the proinflammatory state associated with steatosis. These supplementations trigger different molecular mechanisms that modify antioxidant, antisteatotic, and anti-inflammatory responses, and in the case of DHA and HT co-administration, prevent NAFLD. It is concluded that future studies in NAFLD patients using combined supplementations such as DHA plus HT are warranted to prevent liver steatosis, thus avoiding its progression into more unmanageable stages of the disease.

Protective Effects of Eicosapentaenoic Acid Plus Hydroxytyrosol Supplementation Against White Adipose Tissue Abnormalities in Mice Fed a High-Fat Diet

“…This conclusion is also supported by EPA supplementation to HFD-fed mice showing maintenance of normal adiponectin levels without diminishing adiposity, pointing to adiponectin as a major factor in EPA-mediated prevention and reversal of IR [ 50 ]. Regarding the molecular mechanisms underlying these effects, EPA increase the expression of adiponectin through binding to PPAR-γ, promoting the expression of FGF21 and the activation of AMP-activated protein kinase (AMPK), the energy sensor that favors FAO over lipogenesis [ 15 , 42 , 47 , 51 ]. The EPA-induced AMPK activation by phosphorylation in 3T3-L1 adipocytes [ 51 ] is in agreement with in vivo studies showing that n-3 LCPUFAs increase the content of WAT AMPK α1 subunit and its phosphorylation status, in association with an enhancement in adiponectin levels [ 52 , 53 ].…”

“…Currently, preclinical studies point to the advantage of using combined protocols over monotherapies in the prevention or resolution of metabolic disorders [ 14 , 15 ]. In fact, the co-supplementation protocols are more effective than the single ones, considering that the former exhibit the possibility to exert additive or potentiated responses [ 14 , 16 ].…”

Dysregulated FAM215A Stimulates LAMP2 Expression to Confer Drug-Resistant and Malignant in Human Liver Cancer

“…ERK1/2 also plays an important role in the metabolism of the liver. ERK1/2 can affect liver metabolism by positively affecting the activation of Peroxisome proliferator-activated receptors (PPARs)-alpha, a gene related to liver fat metabolism [41,42]. PPAR is a ligand-activated transcription factor that regulates mitochondrial function, ATP generation, antioxidant, immune responses, and fatty acid oxidation [43].…”

Anti-Inflammatory Effects of Alnus Sibirica Extract on In Vitro and In Vivo Models

“…The modulation of the antioxidant response is directly related to the inflammatory response because the activation of NF-kB is redox-sensitive. Therefore, the potential activation of Nrf2 would generate an inactivation of NF-kB [28].…”