Abstract
Simple SummaryDyslipidemia is a hallmark of nonalcoholic fatty liver disease (NAFLD) and the rs599839 variant in the CELSR2-PSRC1-SORT1 genetic cluster, has been associated with a protection against cardiovascular events. Here, we revealed a novel link between the rs599839 variant and hepatocellular carcinoma (HCC) whose onset in the context of NAFLD is rapidly increasing. We found that the rs599839 variant disentangled the risk of HCC from that of cardiovascular abnormalities by modulating SORT1 and PSRC1 expressions. The latter emerged as a potential modifier of liver carcinogenesis.Background and Aims: Dyslipidemia and cardiovascular diseases (CVD) are comorbidities of nonalcoholic fatty liver disease (NAFLD), which ranges from steatosis to hepatocellular carcinoma (HCC). The rs599839 A>G variant, in the CELSR2-PSRC1-SORT1 gene cluster, has been associated CVD, but its impact on metabolic traits and on the severity liver damage in NAFLD has not been investigated yet. Methods: We evaluated the effect of the rs599839 variant in 1426 NAFLD patients (Overall cohort) of whom 131 had HCC (NAFLD-HCC), in 500,000 individuals from the UK Biobank Cohort (UKBBC), and in 366 HCC samples from The Cancer Genome Atlas (TCGA). Hepatic PSRC1, SORT1 and CELSR2 expressions were evaluated by RNAseq (n = 125). Results: The rs599839 variant was associated with reduced circulating LDL, carotid intima-media thickness, carotid plaques and hypertension (p < 0.05) in NAFLD patients and with protection against dyslipidemia in UKBBC. The minor G allele was associated with higher risk of HCC, independently of fibrosis severity (odds ratio (OR): 5.62; 95% c.i. 1.77–17.84, p = 0.003), poor prognosis and advanced tumor stage (p < 0.05) in the overall cohort. Hepatic PSRC1, SORT1 and CELSR2 expressions were increased in NAFLD patients carrying the rs599839 variant (p < 0.0001). SORT1 mRNA levels negatively correlated with circulating lipids and with those of genes involved in lipoprotein turnover (p < 0.0001). Conversely, PSRC1 expression was positively related to that of genes implicated in cell proliferation (p < 0.0001). In TCGA, PSRC1 over-expression promoted more aggressive HCC development (p < 0.05). Conclusions: In sum, the rs599839 A>G variant is associated with protection against dyslipidemia and CVD in NAFLD patients, but as one it might promote HCC development by modulating SORT1 and PSRC1 expressions which impact on lipid metabolism and cell proliferation, respectively.
Highlights
Nonalcoholic fatty liver disease (NAFLD) or as more recently redefined, metabolicdysfunction associated fatty liver disease (MAFLD), is the most common chronic liver disorder worldwide, affecting an estimated 20–40% of the adult population [1,2]
Since atherogenic dyslipidemia is a hallmark of nonalcoholic fatty liver disease (NAFLD) and the rs599839 variant has been associated with reduced circulating lipids in patients with coronary artery disease (CAD), we firstly aimed to examine the effect of the rs599839 variant on metabolic traits, cardiovascular risk and progressive liver damage in a large histologically characterized cohort of NAFLD patients at risk of cardiovascular comorbidities
Circulating total cholesterol (TC) and low-density lipoprotein (LDL) cholesterol were reduced in NAFLD patients across the rs599839 genotype, while high-density lipoprotein (HDL) cholesterol levels were higher in patients who carry the minor G allele (p < 0.001 at one-way analysis of variance (ANOVA); adjusted p < 0.0001 for GG vs. AA, Figure 1A–C)
Summary
Nonalcoholic fatty liver disease (NAFLD) or as more recently redefined, metabolicdysfunction associated fatty liver disease (MAFLD), is the most common chronic liver disorder worldwide, affecting an estimated 20–40% of the adult population [1,2]. NAFLD is defined by excessive hepatic fat accumulation not explained by alcohol abuse, and it embraces a broad spectrum of hepatic injuries, spanning from simple steatosis to nonalcoholic steatohepatitis (NASH) The latter may be complicated by the development of fibrosis and, in a minor percentage of cases, it may progress to cirrhosis and hepatocellular carcinoma (HCC), that is the fifth most common cancer worldwide with persistently increasing mortality in Europe, North/South America and Africa [4]. The rs599839 A>G variant, in the CELSR2-PSRC1-SORT1 gene cluster, has been associated CVD, but its impact on metabolic traits and on the severity liver damage in NAFLD has not been investigated yet. Hepatic PSRC1, SORT1 and CELSR2 expressions were increased in NAFLD patients carrying the rs599839 variant (p < 0.0001).
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