The interplay between nonalcoholic fatty liver disease and atherosclerotic cardiovascular disease

Abstract

Therapeutic approaches that lower circulating low-density lipoprotein (LDL)-cholesterol significantly reduced the burden of cardiovascular disease over the last decades. However, the persistent rise in the obesity epidemic is beginning to reverse this decline. Alongside obesity, the incidence of nonalcoholic fatty liver disease (NAFLD) has substantially increased in the last three decades. Currently, approximately one third of world population is affected by NAFLD. Notably, the presence of NAFLD and particularly its more severe form, nonalcoholic steatohepatitis (NASH), serves as an independent risk factor for atherosclerotic cardiovascular disease (ASCVD), thus, raising interest in the relationship between these two diseases. Importantly, ASCVD is the major cause of death in patients with NASH independent of traditional risk factors. Nevertheless, the pathophysiology linking NAFLD/NASH with ASCVD remains poorly understood. While dyslipidemia is a common risk factor underlying both diseases, therapies that lower circulating LDL-cholesterol are largely ineffective against NASH. While there are no approved pharmacological therapies for NASH, some of the most advanced drug candidates exacerbate atherogenic dyslipidemia, raising concerns regarding their adverse cardiovascular consequences. In this review, we address current gaps in our understanding of the mechanisms linking NAFLD/NASH and ASCVD, explore strategies to simultaneously model these diseases, evaluate emerging biomarkers that may be useful to diagnose the presence of both diseases, and discuss investigational approaches and ongoing clinical trials that potentially target both diseases.

Post‐nursing early life macronutrient balance promotes persistent and malleable biometric and metabolic traits in mice

“…It will also be important to determine the particular mechanisms involved. A key initial focus should be to understand if the higher serum and liver triglyceride levels are related and the direction of this relationship, especially given that there seems to be an existing relationship between liver and serum triglyceride levels as shown in other studies (Finney et al, 2023). Of note, there was not an effect of early life macronutrient levels on serum and liver cholesterol levels.…”

“…This is consistent with previous studies showing that the gestational and nursing nutritional periods can affect lipid homeostasis in adults (Alfaradhi et al, 2014) and here we show that this is also true for the post-nursing early childhood-adulthood period. This is important as dyslipidaemia is a risk factor for prominent age-related diseases, particularly atherosclerotic cardiovascular disease and non-alcoholic fatty liver disease (Finney et al, 2023). Again, it will be important to determine whether high-fat feeding in this particular early life period stably affects dyslipidaemia-related disease risk in later life using appropriate animal models.…”

What are the common downstream molecular events between alcoholic and nonalcoholic fatty liver?

“…There are conflicting results related to the role of SIRT4 in the development of atherosclerosis, which is strongly associated with NAFLD [ 144 ] and heavy alcohol consumption [ 145 ]. SIRT4 overexpression suppressed the PI3K/Akt/NF‑κB pathway by inhibiting PI3K phosphorylation and phosphorylated (p)‑Akt and inhibiting the expression of inflammatory cytokines in oxidized low-density lipoprotein‑induced human umbilical vein endothelial cells [ 146 ].…”

Metabolic dysfunction-associated steatotic liver disease heterogeneity: Need of subtyping

“…CVD risk increases with the presence of hepatic steatosis and stage of fatty liver disease[ 49 , 50 ]. A meta-analysis of observational studies including 34043 participants with diagnosis of MASLD confirmed an associated higher risk of cardiometabolic complications.…”

“…TM6SF2 rs58542926 T-allele–mediated hepatic retention of TGs and cholesterol predispose patients to MASLD-related fibrosis, whereas C-allele carriage promotes VLDL excretion, thus increasing the risk of CVD or atherosclerosis while protecting the liver[ 43 , 58 ]. Also, similar to TM6SF2 mutation, PNPLA3 rs738409 G allele is associated with a low risk of cardiovascular events, owing to the tight association with lower serum LDL level, as low LDL-C and high HDL-C are cardioprotective[ 50 , 59 ].…”