Georgios Germanidis

The escalating global prevalence of obesity and its intricate association with the development of hepatocellular carcinoma (HCC) pose a substantial challenge to public health. Obesity, acknowledged as a pervasive epidemic, is linked to an array of chronic diseases, including HCC, catalyzing the need for a comprehensive understanding of its molecular underpinnings. Notably, HCC has emerged as a leading malignancy with rising incidence and mortality. The transition from viral etiologies to the prominence of metabolic dysfunction-associated fatty liver disease (MAFLD)-related HCC underscores the urgent need to explore the intricate molecular pathways linking obesity and hepatic carcinogenesis. This review delves into the interwoven landscape of molecular carcinogenesis in the context of obesity-driven HCC while also navigating using the current therapeutic strategies and future prospects for combating obesity-related HCC. We underscore the pivotal role of obesity as a risk factor and propose an integrated approach encompassing lifestyle interventions, pharmacotherapy, and the exploration of emerging targeted therapies. As the obesity-HCC nexus continues to challenge healthcare systems globally, a comprehensive understanding of the intricate molecular mechanisms and innovative therapeutic strategies is imperative to alleviate the rising burden of this dual menace.

Aim: One single nucleotide polymorphism (SNP) rs738409 in the patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene has been considered a major genetic risk factor of nonalcoholic fatty liver disease (NAFLD). Data have indicated that NAFLD is related to insulin resistance and dyslipidemia, but whether rs738409 is associated with circulating lipid and lipoproteins is not fully elucidated. The main aim of this study was to assess the association of rs738409 with lipid and lipoprotein levels in patients with dyslipidemia. Methods: This was a post-hoc analysis of a study in patients with dyslipidemia recruited on an outpatient basis. Morning blood samples were collected after a 12-h fast. Genomic DNA was extracted from whole-blood samples. Results: One hundred seventy-five patients with dyslipidemia were included (97 women). Lipid levels [total cholesterol (TC), triglycerides (TGs), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C)] or glycosylated hemoglobin (HbA1c) were not associated with the SNP, even after adjustment for gender, body mass index (BMI) and type 2 diabetes mellitus (T2DM), using either the additive (CC vs. CG vs. GG) or the dominant (CC vs. GG + CG) inheritance model. When data were stratified for obesity, significant associations between the variant and TC (P = 0.014) or LDL-C levels (P = 0.046) in the non-obese were observed. Pairwise comparison revealed significant changes only in TC between CC and CG genotypes (P = 0.012). Conclusions: No association was shown between rs738409 SNP and lipid/lipoprotein levels in patients with dyslipidemia. In subgroup analysis, TC was higher in non-obese, but not in obese, patients with CC, compared to CG carriers.