Bridging Metabolic-Associated Steatotic Liver Disease and Cardiovascular Risk: A Potential Role for Ketogenesis

The prevalence of cardiovascular diseases (CVDs) is a growing global health concern. Recent advances have demonstrated significant reductions in acute cardiovascular events through the management of modifiable cardiovascular risk factors. However, these factors are responsible for about 50% of the global cardiovascular disease burden. Considering that CVDs are one of the top mortality causes worldwide, the concept of residual cardiovascular risk is an important emerging area of study. Different factors have been proposed as sources of residual risk markers, including non-HDL particles characterization, as well as inflammation measured by serum and imaging technics. Among these, metabolic-associated steatotic liver disease (MASLD) remains controversial. Two opposing viewpoints contend: one positing that fatty liver disease merely reflects classical risk factors and thus adds no additional risk and another asserting that fatty liver disease independently impacts cardiovascular disease incidence. To address this dilemma, one hypothetical approach is to identify specific hepatic energy-yielding mechanisms and assess their impact on the cardiovascular system. Ketogenesis, a metabolic intermediate process particularly linked to energy homeostasis during fasting, might help to link these concepts. Ketogenic metabolism has been shown to vary through MASLD progression. Additionally, newer evidence supports the significance of circulating ketone bodies in cardiovascular risk prediction. Furthermore, ketogenic metabolism modification seems to have a therapeutic impact on cardiovascular and endothelial damage. Describing the relationship, if any, between steatotic liver disease and cardiovascular disease development through ketogenesis impairment might help to clarify MASLD's role in cardiovascular risk. Furthermore, this evidence might help to solve the controversy surrounding liver steatosis impact in CVD and might lead to a more accurate risk assessment and therapeutic targets in the pursuit of precision medicine.