Metabolic-Dysfunction-Associated Steatotic Liver Disease-Its Pathophysiology, Association with Atherosclerosis and Cardiovascular Disease, and Treatments

Abstract

Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a chronic liver disease that affects more than a quarter of the global population and whose prevalence is increasing worldwide due to the pandemic of obesity. Obesity, impaired glucose metabolism, high blood pressure and atherogenic dyslipidemia are risk factors for MASLD. Therefore, insulin resistance may be closely associated with the development and progression of MASLD. Hepatic entry of increased fatty acids released from adipose tissue, increase in fatty acid synthesis and reduced fatty acid oxidation in the liver and hepatic overproduction of triglyceride-rich lipoproteins may induce the development of MASLD. Since insulin resistance also induces atherosclerosis, the leading cause for death in MASLD patients is cardiovascular disease. Considering that the development of cardiovascular diseases determines the prognosis of MASLD patients, the therapeutic interventions for MASLD should reduce body weight and improve coronary risk factors, in addition to an improving in liver function. Lifestyle modifications, such as improved diet and increased exercise, and surgical interventions, such as bariatric surgery and intragastric balloons, have shown to improve MASLD by reducing body weight. Sodium glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been shown to improve coronary risk factors and to suppress the occurrence of cardiovascular diseases. Both SGLT2i and GLP-1 have been reported to improve liver enzymes, hepatic steatosis and fibrosis. We recently reported that the selective peroxisome proliferator-activated receptor-alpha (PPARα) modulator pemafibrate improved liver function. PPARα agonists have multiple anti-atherogenic properties. Here, we consider the pathophysiology of MASLD and the mechanisms of action of such drugs and whether such drugs and the combination therapy of such drugs could be the treatments for MASLD.

Keywords: cardiovascular disease; fatty acids; insulin resistance; metabolic-dysfunction-associated steatotic liver disease; pemafibrate; triglyceride.

Figure 1

The abnormal lipid metabolism possibly induced by insulin resistance and its association with the development of MASLD. Black and white arrows pointing upward and downward indicate an increase or decrease in expression or activity, respectively. Solid black lines indicate the flow of substances and the effects of each metabolic event.

Figure 2

The underlying mechanisms for the improvement of MASLD using pemafibrate. Black arrows and white arrows pointing upward or downward indicate increases or decreases in expression and activity, respectively. Black solid lines indicate the effects of each metabolic event.

Figure 3

The underlying mechanisms for the improvement of MASLD and vascular protection using SGLT2is. Black arrows and white arrows pointing upward or downward indicate increases or decreases in expression and activity, respectively. Black solid lines indicate the effects of each metabolic event.

Figure 4

The underlying mechanisms for MASLD treatment and vascular protection using GLP-1RAs. Black arrows and white arrows pointing upward or downward indicate increases or decreases in expression and activity, respectively. Black solid lines indicate the effects of each metabolic event.

Figure 5

The summary of this review.