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Cellular and molecular alterations in a human hepatocellular in vitro model of nonalcoholic fatty liver disease development and stratification.
Willett, Rose A; Tryndyak, Volodymyr P; Beland, Frederick A; Pogribny, Igor P.
Afiliação
  • Willett RA; Division of Biochemical Toxicology, FDA-National Center for Toxicological Research, Jefferson, Arkansas, USA.
  • Tryndyak VP; Division of Biochemical Toxicology, FDA-National Center for Toxicological Research, Jefferson, Arkansas, USA.
  • Beland FA; Division of Biochemical Toxicology, FDA-National Center for Toxicological Research, Jefferson, Arkansas, USA.
  • Pogribny IP; Division of Biochemical Toxicology, FDA-National Center for Toxicological Research, Jefferson, Arkansas, USA.
Article em En | MEDLINE | ID: mdl-38105681
ABSTRACT
The rapidly increasing incidence of nonalcoholic fatty liver disease (NAFLD) is a growing health crisis worldwide. If not detected early, NAFLD progression can lead to irreversible pathological states, including liver fibrosis and cirrhosis. Using in vitro models to understand the molecular pathogenesis has been extremely beneficial; however, most studies have utilized only short-term exposures, highlighting a limitation in current research to model extended fat-induced liver injury. We treated Hep3B cells continuously with a low dose of oleic and palmitic free fatty acids (FFAs) for 7 or 28 days. Transcriptomic analysis identified dysregulated molecular pathways and differential expression of 984 and 917 genes after FFA treatment for 7 and 28 days respectively. DNA methylation analysis of altered DNA methylated regions (DMRs) found 7 DMRs in common. Pathway analysis of differentially expressed genes (DEGs) revealed transcriptomic changes primarily involved in lipid metabolism, small molecule biochemistry, and molecular transport. Western blot analysis revealed changes in PDK4 and CPT1A protein levels, indicative of mitochondrial stress. In line with this, there was mitochondrial morphological change demonstrating breakdown of the mitochondrial network. This in vitro model of human NAFL mimics results observed in human patients and may be used as a pre-clinical model for drug intervention.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Carcinoma Hepatocelular / Hepatopatia Gordurosa não Alcoólica / Neoplasias Hepáticas Limite: Humans Idioma: En Revista: J Environ Sci Health C Toxicol Carcinog Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Carcinoma Hepatocelular / Hepatopatia Gordurosa não Alcoólica / Neoplasias Hepáticas Limite: Humans Idioma: En Revista: J Environ Sci Health C Toxicol Carcinog Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos