Abstract
Peroxisome proliferator-activated receptors (PPARs) have been suggested to play crucial roles in the pathology of NAFLD with a vague understanding of the underlying mechanism. Here, we integrated large-scale literature data and clinical data to explore the potential role of the PPAR-APOA1 signaling pathway in the pathology of NAFLD. First, the signaling pathway connecting PPARs, APOA1, and NAFLD was constructed. Then, we employed clinical data to explore the association between APOA1 levels and NAFLD. In addition, we built the APOA1-driven pathway analysis to explore the potential mechanism of the APOA1-NAFLD association. Pathway analysis showed that APOA1 serves as a hubprotein connecting PPARs and NAFLD through a beneficial modulation of 16 out of 21 NAFLD upstream regulators. Each relationship within the composed pathway was supported by results from multiple previous studies. Clinical data analysis showed that an increase of APOA1 level was associated with a significantly decreased NAFLD prevalence (χ2 = 292.109; P < 0.001). When other confounding factors were adjusted, serum APOA1 level was shown as an independent risk factor for the prevalence of NAFLD (P value<.0001; OR = 0.562). Our results suggested that the three PPARs (PPARA, PPARD, and PPARG) might promote the expression and molecular transportation of APOA1 to form a PPAR-APOA1 signaling pathway that demonstrated a beneficial role in the pathogenesis of NAFLD.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is characterized by an excessive fat build-up in the liver without a clear cause, such as alcohol use [1, 2]
Our results indicated that the prevalence of NAFLD could decrease with elevated apolipoprotein A1 (APOA1) levels, and that low serum APOA1 levels might be an independent risk factor for the prevalence of NAFLD
4), the influence of APOA1 levels was statistically significant in all models with/without adjusting other confounding factors. These results indicated that the increased serum APOA1 levels could be more critical than the deficiency of serum APOA1 in their influence on NAFLD development
Summary
Nonalcoholic fatty liver disease (NAFLD) is characterized by an excessive fat build-up in the liver without a clear cause, such as alcohol use [1, 2]. NAFLD is known as a metabolic dysfunction-associated fatty liver disease that has two subtypes, nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). Peroxisome proliferator-activated receptors have been suggested to play crucial roles in the pathology of NAFLD [5, 6]. Peroxisome proliferator-activated receptor γ (PPARG) has been shown essential to protect against nonalcoholic steatohepatitis [6]. As the major component of high-density lipoprotein (HDL) particles, apolipoprotein A1 (APOA1) is a protein encoded by the APOA1 gene to have a specific role in lipid metabolism [10, 11]. All three PPARs (PPARA, PPARD, and PPARG) were implicated as promoters to increase APOA1 secretion and expression from the liver [16,17,18], which may partially decode the role of PPARs in NAFLD. We employed large-scale literature-based pathway analysis and clinical data analysis to explore the role of the PPAR-APOA1 signaling pathway in NAFLD, which may add new insights into the understanding of the NAFLD treatment
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