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Permethrin and ivermectin modulate lipid metabolism in steatosis-induced HepG2 hepatocyte.

ABSTRACT: Recent studies have reported the positive association between exposure to insecticides and increased risk of obesity and type 2 diabetes, which are closely associated with non-alcoholic fatty liver disease (NAFLD). However, it is not known if insecticide exposure can contribute to NAFLD. Thus, the goal of the current study was to determine if insecticide exposures can exacerbate the physiological conditions of NAFLD by modulating hepatic lipid metabolism. The effects of 12 insecticides on triglycerides (TG) accumulation were tested using palmitic acid (PA)-induced HepG2 hepatoma steatosis model. Results showed that among tested insecticides, permethrin and ivermectin significant interacted with palmitic acid to potentiate (permethrin) or decrease (ivermectin) TG accumulation. Further study showed that permethrin significantly promoted fatty acid synthesis, while suppressed lipid oxidation-related genes only under steatosis conditions. In comparison, ivermectin inhibited lipogenesis-related genes and promoted farnesoid X receptor, which upregulates fatty acid oxidation. Results in this study suggested that hepatic lipid metabolism may be more susceptible to insecticide exposure in the presence of excessive fatty acids, which can be associated with the development of NAFLD.

SUBMITTER: Yang JS

PROVIDER: S-EPMC6527113 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Permethrin and ivermectin modulate lipid metabolism in steatosis-induced HepG2 hepatocyte.

Yang Jason S JS Qi Weipeng W Farias-Pereira Renalison R Choi Stephanie S Clark John M JM Kim Daeyoung D Park Yeonhwa Y

Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 20190206

Recent studies have reported the positive association between exposure to insecticides and increased risk of obesity and type 2 diabetes, which are closely associated with non-alcoholic fatty liver disease (NAFLD). However, it is not known if insecticide exposure can contribute to NAFLD. Thus, the goal of the current study was to determine if insecticide exposures can exacerbate the physiological conditions of NAFLD by modulating hepatic lipid metabolism. The effects of 12 insecticides on trigly ...[more]

PMID: 30738135

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Project description:Chronic alcohol causes hepatic steatosis and liver hypoxia. Hypoxia-regulated hypoxia-inducible factor 1-?, (HIF-1?) may regulate liporegulatory genes, but the relationship of HIF-1 to steatosis remains unknown. We investigated HIF-1? in alcohol-induced hepatic lipid accumulation. Alcohol administration resulted in steatosis, increased liver triglyceride levels, and increased serum alanine aminotransferase (ALT) levels, suggesting liver injury in wild-type (WT) mice. There was increased hepatic HIF-1? messenger RNA (mRNA), protein, and DNA-binding activity in alcohol-fed mice compared with controls. Mice engineered with hepatocyte-specific HIF-1 activation (HIF1dPA) had increased HIF-1? mRNA, protein, and DNA-binding activity, and alcohol feeding in HIF1dPA mice increased hepatomegaly and hepatic triglyceride compared with WT mice. In contrast, hepatocyte-specific deletion of HIF-1? [HIF-1?(Hep(-/-) )], protected mice from alcohol- and lipopolysaccharide (LPS)-induced liver damage, serum ALT elevation, hepatomegaly, and lipid accumulation. HIF-1?(Hep(-/-) ), WT, and HIF1dPA mice had equally suppressed levels of peroxisome proliferator-activated receptor ? mRNA after chronic ethanol, whereas the HIF target, adipocyte differentiation-related protein, was up-regulated in WT mice but not HIF-1?(Hep(-/-) ) ethanol-fed/LPS-challenged mice. The chemokine monocyte chemoattractant protein-1 (MCP-1) was cooperatively induced by alcohol feeding and LPS in WT but not HIF-1?(Hep(-/-) ) mice. Using Huh7 hepatoma cells in vitro, we found that MCP-1 treatment induced lipid accumulation and increased HIF-1? protein expression as well as DNA-binding activity. Small interfering RNA inhibition of HIF-1? prevented MCP-1-induced lipid accumulation, suggesting a mechanistic role for HIF-1? in hepatocyte lipid accumulation.Alcohol feeding results in lipid accumulation in hepatocytes involving HIF-1? activation. The alcohol-induced chemokine MCP-1 triggers lipid accumulation in hepatocytes via HIF-1? activation, suggesting a mechanistic link between inflammation and hepatic steatosis in alcoholic liver disease.

Project description:BACKGROUND:Lipogenesis is required for the optimal growth of many types of cancer cells, it is shown to control the biosynthesis of the lipid bilayer membrane during rapid proliferation and metastasis, provides cancer cells with signaling lipid molecules to support cancer development and make cancer cells more resistant to oxidative stress-induced cell death. Though multiple lipogenic enzymes have been identified to mediate this metabolic change, how the expression of these lipogenic enzymes are transcriptionally regulated remains unclear. METHODS:Gain- and loss-of-function experiments were conducted to assess the role of transcriptional repressor, nuclear receptor sub-family 6, group A, member 1 (NR6A1) in HepG2 cells. RT-qPCR method was performed to investigate target gene of NR6A1. Western blot was employed to determine the mechanisms by which NR6A1 regulates lipid accumulation in HepG2 cells. RESULTS:We provide evidence that NR6A1 is a novel regulator of lipid metabolism in HepG2 cells. NR6A1 knockdown can increase lipid accumulation as well as insulin-induced proliferation and migration of HepG2 cells. The lipogenic effect correlated well with the expression of lipogenic genes, including fatty acid synthase (FAS), diglyceride acyltransferase-2 (DGAT2), malic enzyme 1 (ME1), microsomal triglyceride transfer protein (MTTP) and phosphoenolpyruvate carboxykinase (PEPCK). NR6A1 knockdown also increased the expression of carnitine palmitoyltransferase 1A (CPT1a), the rate-limiting enzyme in fatty acid oxidation. Furthermore, NR6A1 knockdown induced lipid accumulation through mammalian target of rapamycin complex 1 (mTORC1), but not mTORC2. Moreover, siRNA-mediated knockdown of NR6A1 increased expression of insulin receptor (INSR) and potentitated insulin-induced phosphorylation of mTOR and AKT partly via miR-205-5p in HepG2 cells. CONCLUSIONS:These findings provide important new insights into the role of NR6A1 in the lipogenesis in HepG2 cells. .

Dataset Information

Permethrin and ivermectin modulate lipid metabolism in steatosis-induced HepG2 hepatocyte.

Publications

Permethrin and ivermectin modulate lipid metabolism in steatosis-induced HepG2 hepatocyte.

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