👤 Matteo Pedrelli

This review examines whether high high-density lipoprotein cholesterol (HDL-C) is protective, harmful, or simply misleading in relation to atherosclerotic cardiovascular disease (ASCVD), with emphasis on recent mechanistic, epidemiologic, genetic, and trial evidence. HDL is biologically important and multifunctional, but HDL-C is an imperfect surrogate for HDL function. Recent cohort studies show nonlinear associations, with very high HDL-C not consistently protective and in some settings associated with increased mortality. Mendelian randomization studies do not support HDL-C as a causal protective factor, and randomized trials of HDL-C-raising strategies have generally failed to reduce ASCVD events. These findings have shifted attention from HDL quantity to HDL quality, including cholesterol efflux capacity, particle characteristics, and pathway-specific biology. At the same time, modern cholesteryl ester transfer protein (CETP) inhibition has renewed interest in whether benefit, if any, relates to Apolipoprotein B-lowering rather than HDL-C elevation itself. HDL biology remains highly relevant, but HDL-C alone should not be interpreted as a reliable marker of atheroprotection or as a therapeutic target. Very high HDL-C should not be used to downplay established causal risk factors. Future research should prioritize functional HDL metrics, deeper phenotyping, and mechanism-aligned trials to determine whether improving HDL quality, rather than simply raising HDL-C, can reduce ASCVD risk. Show less

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver condition globally, driven by strong genetic and environmental components. This review summarizes recent advances in understanding the genetic architecture of MASLD. Genome-wide association studies (GWAS) have identified several key risk variants, primarily in genes such as Show less

The liver plays a pivotal role in the physiological adaptation to fasting and a better understanding of the metabolic adaptive responses may give hints on new therapeutic strategies to control the metabolic diseases. The liver X receptors (LXRs) are well-established regulators of lipid and glucose metabolism. More recently fibroblast growth factor 21 (FGF21) has emerged as an important regulator of energy homeostasis. We hypothesized that the LXR transcription factors could influence Fgf21 expression, which is induced in response to fasting. Wild-type, LXRα(-/-), and LXRβ(-/-) mice were treated for 3 d with vehicle or the LXR agonist GW3965 and fasted for 12 h prior to the killing of the animals. Interestingly, serum FGF21 levels were induced after fasting, but this increase was blunted when the mice were treated with GW3965 independently of genotypes. Compared with wild-type mice, GW3965-treated LXRα(-/-) and LXRβ(-/-) mice showed improved insulin sensitivity and enhanced ketogenic response at fasting. Of note is that during fasting, GW3965 treatment tended to reduce liver triglycerides as opposed to the effect of the agonist in the fed state. The LXR-dependent repression of Fgf21 seems to be mainly mediated by the recruitment of LXRβ onto the Fgf21 promoter upon GW3965 treatment. This repression by LXRβ occurs through the recruitment and stabilization of the repressor complex composed of retinoid-related orphan receptor-α/Rev-Erbα/histone deacetylase 3 onto the Fgf21 promoter. Our data clearly demonstrate that there is a cross talk between the LXR and FGF21 signaling pathways in the adaptive response to fasting. Show less