Drivers of cardiovascular disease in metabolic dysfunction-associated steatotic liver disease: the threats of oxidative stress

Abstract

Non-alcoholic fatty liver disease (NAFLD), now known as metabolic-associated steatotic liver disease (MASLD), is the most common liver disease worldwide, with a prevalence of 38%. In these patients, cardiovascular disease (CVD) is the number one cause of mortality rather than liver disease. Liver abnormalities per se due to MASLD contribute to risk factors such as dyslipidemia and obesity and increase CVD incidents. In this review we discuss hepatic pathophysiological changes the liver of MASLD leading to cardiovascular risks, including liver sinusoidal endothelial cells, insulin resistance, and oxidative stress with a focus on glutathione metabolism and function. In an era where there is an increasingly robust recognition of what causes CVD, such as the factors included by the American Heart Association in the recently developed PREVENT equation, the inclusion of liver disease may open doors to how we approach treatment for MASLD patients who are at risk of CVD.

Keywords: MASLD; cardiovascular risk; glutathione; insulin resistance; liver sinusoid; oxidative stress; remdesivir; steatosis.

Figure 1

New nomenclature and criteria. Transition from the old NAFLD nomenclature to the new MASLD terminology, highlighting key differences in diagnostic criteria. The old NAFLD criteria focused primarily on hepatic steatosis whereas the new MASLD criteria take into account a broader range of metabolic risk factors.

Figure 2

Liver sinusoidal endothelial cells (LSECs) in MASLD. Normal LSEC has a unique fenestrae by which macromolecules may transfer between the bloodstream and space of Disse (space between hepatocytes and sinusoid). LSEC reduces fenestrae and differentiates or capillarizes in the liver of MASLD. In the presence of normal LSEC, triglyceride-rich chylomicron remnants are removed from the bloodstream (vascular lumen → fenestrae → space of Disse). Similarly, VLDL enters the bloodstream via LSEC fenestrae. With the loss of fenestrae, both of these processes are impaired, driving atherosclerosis and hepatic steatosis respectively.

Figure 3

Insulin resistance in MASLD. One major consequence of steatosis is hepatic insulin resistance. In one of the mechanism, this can occur via PKCε mediated inhibition of IRS2 phosphorylation, thus dampening the effects of insulin. This impairment drives hyperglycemia and hyperinsulinemia, which in turn stimulate de novo lipogenesis, exacerbate fat accumulation in the liver and perpetuate a detrimental cycle affecting systemic metabolism. DNL, de novo lipogenesis; PKC, protein kinase C; DAG, diacylglycerol; IRS, insulin receptor substrate.

Figure 4

GSH metabolism and function. This illustrates GSH synthesis and recycles in the cells and its molecular functions. Oxidized GSH (GSSG) may cause oxidative stress, but other roles are protective from oxidative stress and help to maintain redox homeostasis. GSH, glutathione; GSSG, oxidized glutathione; Cys, cysteine; Glu, glutamic acid; Gly, glycine; GCL, glutamate-cysteine ligase; GS, glutathione synthetase; GGT, gamma-glutamyl transferase; DP, dipeptidases; GPx, glutathione peroxidase; GSH-R, glutathione reductase; Glrx, glutaredoxin; P-SSG, glutathionylated protein; H₂O₂, hydrogen peroxide; ROS, reactive oxygen species.

Figure 5

Summary: connection from MASLD to CVD. Lipid accumulation causes morphological and physiological changes at cellular levels in the liver, leading systemic effects which are CVD risk factors. Summary of the review is shown.

Figure 6

Redox signaling. (1) Protein thiol oxidation, leading to sulfenylation (P-SOH) or nitrosylation (P-SNO). (2) React with abundant cellular GSH to form protein S-glutathionylation (P-SSG, protein-bound GSH). (3) S-glutathionylaton can be reduced by glutaredoxin-1 (Glrx). This cycle generates reversible protein function and causes cellular signaling, preventing irreversible damage of the protein. (4) Strong oxidative stress causes irreversible oxidation (e.g., sulfonylation; P-SO3H), resulting in protein dysfunction or degradation (left side).