A Novel Mechanism of Monoethylhexyl Phthalate in Lipid Accumulation via Inhibiting Fatty Acid Beta-Oxidation on Hepatic Cells

Abstract

Monoethylhexyl phthalate (MEHP) is one of the main active metabolites of the plasticizer di(2-ethylhexyl) phthalate. It has been known that MEHP has an impact on lipolysis; however, its mechanism on the cellular lipid metabolism remains largely unclear. Here, we first utilized global lipid profiling to fully characterize the lipid synthesis and degradation pathways upon MEHP treatment on hepatic cells. Meanwhile, we further identified the possible MEHP-targeted proteins in living cells using the cellular thermal shift assay (CETSA) method. The lipidomics results showed that there was a significant accumulation of fatty acids and other lipids in the cell. The CETSA identified 18 proteins and fatty acid β-oxidation inhibition pathways that were significantly perturbed. MEHP's binding with selected proteins HADH and HSD17B10 was further evaluated using molecule docking, and results showed that MEHP has higher affinities as compared to endogenous substrates, which was further experimentally confirmed in the surface plasma resonance interaction assay. In summary, we found a novel mechanism for MEHP-induced lipid accumulation, which was probably due to its inhibitive effects on the enzymes in fatty acid β-oxidation. This mechanism substantiates the public concerns on the high exposure level to plasticizers and their possible role as an obesogen.

3-tert-Butyl-4-hydroxyanisole Impairs Hepatic Lipid Metabolism in Male Mice Fed with a High-Fat Diet

“…15140122, Gibco, USA) at 37 °C in a humidified atmosphere with 5% CO 2 . Considering that HepG2 can exert the normal hepatocyte-specific functions, such as lipoprotein transport, cholesterol and triglyceride metabolism, and so on, and it has been characterized as a metabolically relevant model feasible for omics and toxicological studies, − this cell line was consequently used as the in vitro assay for 3-BHA-induced lipid accumulation herein.…”

Neisseria species as pathobionts in bronchiectasis

“…Lung tissue or serum metabolite (Ivanisevic et al, 2013) and lipid (Chen et al, 2013;Xu et al, 2020) extraction methods were obtained from prior studies. For the lung tissue samples, weighted ($10 mg) freeze-tissue samples were homogenized using steel beads with thaw twice.…”

System Biology-Guided Chemical Proteomics to Discover Protein Targets of Monoethylhexyl Phthalate in Regulating Cell Cycle

“…The Centers for Disease Control and Prevention (CDC, US) has reported that MEHP is widely detected in human urine with concentrations ranging from 14.1 to 39.7 μg/L in the US population . There is strong evidence suggesting that MEHP possesses endocrine-disrupting and obesogenic effects on human health, disturbs the energy balance due to its activation effect on peroxisome proliferator-activated receptor γ (PPAR-γ), , and inhibits fatty acid oxidation, according to our recent study . Although MEHP affects different physiological functions, its toxic mechanisms and roles in the cellular system remain largely elusive.…”

“…22 There is strong evidence suggesting that MEHP possesses endocrine-disrupting and obesogenic effects on human health, disturbs the energy balance due to its activation effect on peroxisome proliferator-activated receptor γ (PPAR-γ), 23,24 and inhibits fatty acid oxidation, according to our recent study. 25 Although MEHP affects different physiological functions, its toxic mechanisms and roles in the cellular system remain largely elusive. The various adverse effects caused by MEHP, therefore, is likely attributed to its multiple protein targets contributing to the toxicity.…”