Hexanoic, Octanoic and Decanoic Acids Promote Basal and Insulin-Induced Phosphorylation of the Akt-mTOR Axis and a Balanced Lipid Metabolism in the HepG2 Hepatoma Cell Line

Abstract

Metabolic illnesses such as non-alcoholic fatty liver disease (NAFLD) are in constant increase worldwide. Highly consumed long chain fatty acids (LCFA) are among the most obesogenic and steatogenic nutrients. Hepatic steatosis is associated with several complications such as insulin resistance. Growing evidence points to medium chain fatty acids (MCFA), more efficiently oxidized than LCFA, as a promising dietary alternative against NAFLD. However, reports on the hepatic effects of MCFA are sometimes conflicting. In this study we exposed HepG2 cells, a human hepatocellular model, to 0.25 mM of hexanoic (C6), or octanoic (C8), and decanoic (C10) acids separately or in a C8 + C10 equimolar mix reflecting commercially available MCFA-rich oils. We found that C6, a poorly studied MCFA, as well as C8 and C10 did not provoke the deleterious lipid anabolism runaway typically induced by LCFA palmitate. MCFA tended, instead, to promote a balanced metabolic profile and were generally non-cytotoxic. Accordingly, mitochondrial integrity was mostly preserved following MCFA treatment. However, treatments with C8 induced a mitochondrial membrane potential decrease, suggesting prolonged exposure to this lipid could be problematic. Finally, MCFA treatments maintained optimal insulin sensitivity and even fostered basal and insulin-dependent phosphorylation of the Akt-mTOR pathway. Overall, MCFA could constitute an effective nutritional tool to manage liver steatosis and hepatic insulin resistance.

Effect of Carotenoids from Phaeodactylum tricornutum on Palmitate-Treated HepG2 Cells

“…Firstly, PAL is known to increase lipid storage in the liver by a process mainly controlled by the SREBF1 transcription factor [ 51 ]. In accordance with the present study, previous studies using HepG2 cells treated for 24 h with palmitate at 250 µM or 300 µM showed an increase in the expression of enzymes involved in the oxidation and de novo synthesis of fatty acids such as CPT1A and SCD [ 41 , 52 ]. Although our analyses showed no significant change in the mRNA levels of lipogenic genes ( ACACA , DGAT1 , FASN and LXR/NR1H3 ) in our cellular model of NAFLD, the mRNA levels of CPT2 and ACAT1 / SOAT1 were increased in agreement with in vivo studies [ 53 , 54 ].…”

“…In agreement with several studies [40][41][42], PAL-treated HepG2 cells showed a significant increase in lipid droplet accumulation and the cellular levels of triglycerides, total cholesterol and cholesterol esters. Both extracts prevented the elevation of triglyceride, total cholesterol and cholesterol ester levels in HepG2 cells.…”

“…The aim of this study was to investigate the impact of CE from P. tricornutum on NAFLD and associated metabolic pathways, in human liver HepG2 cells. Twenty-four hours of PAL treatment at a concentration of 250 μM is well known to induce NAFLD without altering cell viability in HepG2 cells [ 40 , 41 , 42 , 43 , 44 ]. To assess the protective effects of microalga extracts on PAL-induced NAFLD, extracts have to be used at non-toxic concentrations.…”

“…The retained cellular model was the human hepatocarcinoma HepG2 cell line, which is commonly used to study lipid metabolism and metabolic disturbances in the liver, particularly those associated with NAFLD [38,39]. NAFLD was simulated by the treatment of cells with 250 µM palmitate for 24 h, as commonly used to induce lipotoxicity and hepatic steatosis in HepG2 cells [40][41][42].…”

Recent Advances in the Pathophysiology of Fatty Acid Oxidation Defects: Secondary Alterations of Bioenergetics and Mitochondrial Calcium Homeostasis Caused by the Accumulating Fatty Acids

“…Calcium retention capacity was also decreased by DA and cDA, probably as a result of mPT induction in the liver mitochondria (Amaral et al, 2016). Other studies reported that OA and DA caused m dissipation in hepatocytes (Rial et al, 2018) and induced apoptosis in adipocytes (Yang et al, 2009), whereas OA was demonstrated to decrease the ATP/O ratio in perfused liver, indicating OXPHOS impairment (Gallis et al, 2007). In contrast, the carnitine derivatives of the corresponding MCFA tested, OC and DC, caused no changes in the mitochondrial parameters evaluated, implying that medium-chain acylcarnitine derivatives do not disturb these mitochondrial functions.…”