| dc.description.abstract | Metabolic-dysfunction associated steatotic liver disease (MASLD), formerly NAFLD, is a major
liver condition linked to obesity, affecting around 30% of adults globally. Steatosis, the
earliest stage of MASLD, progresses to inflammation, fibrosis, and hepatocellular carcinoma if
left untreated. Understanding the role of adipose tissue, particularly subcutaneous white adipose
tissue (scWAT), in the development of steatosis is crucial, as its dysfunction may contribute to
ectopic fat deposition in the liver.
This study aimed to elucidate the molecular mechanisms of steatosis by performing a crosstissue
transcriptomic analysis of scWAT and liver tissue in obese individuals. In addition,
exome-wide association studies (EWAS) and expression quantitative trait loci (eQTL) mapping
were used to identify genetic variants linked to liver fat accumulation and MASLD progression.
We studied 80 obese individuals with liver biopsies from the FATe cohort. RNA-seq was performed
on scWAT and liver samples to assess differential gene expression, while whole exome
sequencing (WES) was used to identify genetic variants. Differential expression analysis was
conducted using DESeq2, and eQTL mapping employed MatrixEQTL. Pathway enrichment
analysis was used to investigate the biological processes associated with steatosis.
Transcriptomic analysis revealed that, in scWAT, key genes involved in lipid metabolism, cellular
structure, and adipocyte function were significantly dysregulated in individuals with high
liver steatosis. Notably, genes regulating adipocyte expansion and negative regulation of cell
growth were upregulated, indicating adipose tissue dysfunction. In liver tissue, genes associated
with lipid uptake and storage were upregulated, while those involved in detoxification pathways
were downregulated. EWAS identified genetic loci including S100A7, KIRREL3, USP30, and
SPNS3, which are linked to lipid metabolism, inflammation, and mitochondrial function. eQTL
analysis further uncovered variants regulating key genes such as ETS2 and MSR1, both involved
in macrophage activity and inflammation.
Our findings highlight the critical role of scWAT in the early development of steatosis, with
dysregulated adipose tissue function potentially contributing to ectopic fat deposition in the
liver. The identification of specific genetic variants and dysregulated pathways in scWAT and
liver provides valuable insights into MASLD progression and offers potential targets for future
therapeutic interventions. | es |
