Energy metabolism alteration and gene expression reprogramming in a cell model of high fat load non-alcoholic fatty liver disease

TL;DR

This study explores how high fat exposure changes energy metabolism and gene activity in liver cells, offering insights into early non-alcoholic fatty liver disease development.

Contribution

The study identifies specific gene and protein changes linked to mitochondrial function in early NAFL pathogenesis.

Findings

Fatty acid-treated cells showed a shift to mitochondrial respiration with reduced glycolytic ATP production.

149 transcripts and 172 proteins were altered, with ACAA2 and PLIN2 showing significant changes at both levels.

Lipid storage and catabolism gene reprogramming is crucial for early NAFL development.

Abstract

Metabolic rewiring plays a crucial role in the energy metabolism of hepatocytes during steatosis. However, the precise alterations in energy metabolism remain unclear. The aim of this study was to investigate the effects of lipid exposure on cellular energy metabolism and gene expression in a cellular model of non-alcoholic fatty liver disease (NAFLD).

We induced hepatocyte steatosis in the hepatocyte cell line Huh7 via treatment with high levels of palmitate and oleate for 24 h. We then analysed transcriptomics, proteomics, mitochondrial phenotypes, and cellular energy metabolism. Fatty acid-treated cells presented significant accumulation of lipid droplets and reduced viability. Real-time bioenergetics analyses demonstrated a shift towards mitochondrial respiration for energy production, accompanied by a reduction in glycolytic adenosine triphosphate (ATP) production. However, the overall rate of ATP production remained constant. RNA-seq analysis revealed altered expression of 149 transcripts associated with lipid storage and catabolism, whereas 172 proteins presented significantly altered levels and were enriched in RNA processing and splicing functions. Two genes, ACAA2 and PLIN2, were significantly altered at both the transcript and protein levels and may be crucial for maintaining mitochondrial function in early non-alcoholic fatty liver (NAFL).

Our NAFLD model demonstrated that the reprogramming of genes involved in lipid storage and catabolism is crucial for early NAFL pathogenesis development. This study offers new insights with valuable implications for designing future research into novel therapeutic strategies.

The online version contains supplementary material available at 10.1186/s12876-026-04658-z.

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