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Palmitic Acid-Enriched Diet Induces Hepatic Steatosis and Injury in Adult Zebrafish.

ABSTRACT: Palmitic acid (PA) is the most abundant saturated fatty acid in fast foods and is known to induce inflammation and cellular injury in various tissues. In this study, we investigated whether a PA-enriched diet can induce hepatic steatosis and injury in adult zebrafish. The adult zebrafish exhibited increased body weight, hyperlipidemia, hyperglycemia, and steatosis and a hepatic injury phenotype after being fed with a PA-enriched diet for 6 weeks. The quantitative polymerase chain reaction analysis demonstrated that genes associated with hepatic injury were all significantly increased in the liver. Furthermore, livers from the PA-fed group showed an increased messenger RNA (mRNA) expression associated with oxidative stress and endoplasmic reticulum (ER) stress responses. We also found significant upregulation of genes involved in lipid metabolism and triacylglyceride accumulation. Ultrastructural analysis revealed mitochondrial cristae injury and a dilated ER phenotype in the PA-fed hepatocytes, which can be causes of hepatic injury. PA-enriched diet induced hepatic steatosis and injury in adult zebrafish that recapitulated typical metabolic changes and pathophysiological changes as well as increased oxidative stress and ER stress observed in patients with nonalcoholic fatty liver disease.

SUBMITTER: Park KH

PROVIDER: S-EPMC6916734 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Palmitic Acid-Enriched Diet Induces Hepatic Steatosis and Injury in Adult Zebrafish.

Park Ki-Hoon KH Ye Zhi-Wei ZW Zhang Jie J Kim Seok-Hyung SH

Zebrafish 20190729 6

Palmitic acid (PA) is the most abundant saturated fatty acid in fast foods and is known to induce inflammation and cellular injury in various tissues. In this study, we investigated whether a PA-enriched diet can induce hepatic steatosis and injury in adult zebrafish. The adult zebrafish exhibited increased body weight, hyperlipidemia, hyperglycemia, and steatosis and a hepatic injury phenotype after being fed with a PA-enriched diet for 6 weeks. The quantitative polymerase chain reaction analys ...[more]

PMID: 31355732

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Project description:Nonalcoholic fatty liver disease (NAFLD) is one of the common diseases in the world, and it can progress from simple lipid accumulation to sustained inflammation. The present study was designed to investigate the effects and underlying mechanisms of ginsenoside Rg1 (G-Rg1) treatment on NAFLD in vitro. HepG2 cells were treated with palmitic acid (PA) to induce steatosis and inflammation and then successively incubated with G-Rg1. Lipids accumulation was analyzed by Oil Red O staining and intracellular triglyceride (TG) quantification. Inflammatory conditions were examined by quantifying the levels of cell supernatant alanine transaminase/aspartate aminotransferase (ALT/AST) and secretory proinflammatory cytokines, including IL-1?, IL-6, and TNF-? in the cell supernatants. Quantitative RT-PCR and western blotting were used to measure the expressions of genes and proteins associated with lipogenic synthesis and inflammation, including AMP-activated protein kinase (AMPK) and nuclear factor-kappa B (NF-?B) pathways. HepG2 cells were pretreated with an AMPK inhibitor; then, Oil Red O staining and TG quantification were performed to study the lipid deposition. Phospho-AMPK (Thr172) (p-AMPK) and phospho-acetyl-CoA carboxylase (Ser79) (p-ACC?) were quantified by immunoblotting. Immunofluorescence was performed to demonstrate the nuclear translocation of NF-?B P65. The present study showed that PA markedly increased the intracellular lipid droplets accumulation and TG levels, but decreased AMPK phosphorylation and the expressions of its downstream lipogenic genes. However, G-Rg1 alleviated hepatic steatosis and reduced the intracellular TG content; these changes were accompanied by the activation of the AMPK pathway. In addition, blocking AMPK by using the AMPK inhibitor markedly abolished the G-Rg1-mediated protection against PA-induced lipid deposition in HepG2 cells. Furthermore, G-Rg1 reduced the ALT/AST levels and proinflammatory cytokines release, which were all enhanced by PA. These effects were correlated with the inactivation of the NF-?B pathway and translocation of P65 from the cytoplasm to the nucleus. Overall, these results suggest that G-Rg1 effectively ameliorates hepatic steatosis and inflammation, which might be associated with the AMPK/NF-?B pathway.

Project description:BackgroundHepatic steatosis is an early pathology of alcohol-associated liver disease (ALD). Fatty acid-binding protein-4 (FABP4, a FABP not normally produced in the liver) is secreted by hepatocytes in ALD and stimulates hepatoma proliferation and migration. This study sought to investigate the mechanism[s] by which hepatic ethanol metabolism regulates FABP4 and steatosis.MethodsHuman hepatoma cells (HepG2/HuH7) and cells stably transfected to express cytochrome P450 2E1 (CYP2E1), were exposed to ethanol in the absence or presence of chlormethiazole (a CYP2E1-inhibitor; CMZ) and/or EX-527 (a sirtuin-1 [SIRT1] inhibitor). The culture medium was analyzed for ethanol metabolism and FABP4 protein abundance. Cells were analyzed for FABP4 mRNA expression, SIRT1 protein abundance, and neutral lipid accumulation. In parallel, cells were analyzed for forkhead box O1 [FOXO1], β-catenin, peroxisome proliferator-activated receptor-α [PPARα], and lipin-1α protein abundance in the absence or presence of ethanol and pharmacological inhibitors of the respective target proteins.ResultsCYP2E1-dependent ethanol metabolism inhibited the amount of SIRT1 protein detected, concomitant with increased FABP4 mRNA expression, FABP4 protein secretion, and neutral lipid accumulation, effects abolished by CMZ. Analysis of pathways associated with lipid oxidation revealed increased FOXO1 nuclear localization and decreased β-catenin, PPARα, and lipin-1α protein levels in CYP2E1-expressing cells in the presence of ethanol. Pharmacological inhibition of SIRT1 mimicked the effects of ethanol, while inhibition of FOXO1 abrogated the effect of ethanol on FABP4 mRNA expression, FABP4 protein secretion, and neutral lipid accumulation in CYP2E1-expressing cells. Pharmacological inhibition of β-catenin, PPARα, or lipin-1α failed to alter the effects of ethanol on FABP4 or neutral lipid accumulation.ConclusionCYP2E1-dependent ethanol metabolism inhibits SIRT1-FOXO1 signaling, which leads to increased FABP4 mRNA expression, FABP4 protein secretion, and neutral lipid accumulation. These data suggest that FABP4 released from steatotic hepatocytes could play a role in promoting tumor cell expansion in the setting of ALD and represents a potential target for therapeutic intervention.

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Palmitic Acid-Enriched Diet Induces Hepatic Steatosis and Injury in Adult Zebrafish.

Publications

Palmitic Acid-Enriched Diet Induces Hepatic Steatosis and Injury in Adult Zebrafish.

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