Functional lipids in experimental models of hepatic steatosis (MASLD)

Abstract

Background

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide and is characterized by hepatic steatosis associated with overweight/obesity, type 2 diabetes mellitus, or metabolic dysregulation. Disease progression may lead to steatohepatitis, fibrosis and ultimately cirrhosis. MASLD affects approximately 25% of the global population, and its prevalence continues to increase, representing an important public health challenge. Dietary interventions have emerged as promising strategies to mitigate MASLD by modulating metabolic and epigenetics pathways involved in disease progression. Functional lipids (FL), including n-3 polyunsaturated fatty acids (PUFAs), n-3 long chain-PUFAs, conjugated linoleic acid (CLA), tocopherols (TP), phytosterols (PS), have been shown to regulate gene expression through epigenetic mechanisms, contributing to reduced hepatic lipid accretion, improved glucose homeostasis, and attenuated inflammation.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide and is characterized by hepatic steatosis associated with overweight/obesity, type 2 diabetes mellitus, or metabolic dysregulation. Disease progression may lead to steatohepatitis, fibrosis and ultimately cirrhosis. MASLD affects approximately 25% of the global population, and its prevalence continues to increase, representing an important public health challenge. Dietary interventions have emerged as promising strategies to mitigate MASLD by modulating metabolic and epigenetics pathways involved in disease progression. Functional lipids (FL), including n-3 polyunsaturated fatty acids (PUFAs), n-3 long chain-PUFAs, conjugated linoleic acid (CLA), tocopherols (TP), phytosterols (PS), have been shown to regulate gene expression through epigenetic mechanisms, contributing to reduced hepatic lipid accretion, improved glucose homeostasis, and attenuated inflammation.

Objective

To discuss and integrate current evidence of our group on the potential synergistic protective effects of FL combinations against MASLD, and to summarize the biochemical and molecular mechanisms involved in their beneficial actions.

To discuss and integrate current evidence of our group on the potential synergistic protective effects of FL combinations against MASLD, and to summarize the biochemical and molecular mechanisms involved in their beneficial actions.

Methods

Experimental rodents were fed control or different high-fat diets with or without FL combinations. Nutritional, biochemical, and nutrigenomic analyses were performed in serum, liver, adipose tissue and skeletal muscle to investigate the underlying mechanisms involved in the beneficial effects of FL combinations.

Experimental rodents were fed control or different high-fat diets with or without FL combinations. Nutritional, biochemical, and nutrigenomic analyses were performed in serum, liver, adipose tissue and skeletal muscle to investigate the underlying mechanisms involved in the beneficial effects of FL combinations.

Results

The combination of TP with either n-3 PUFA or CLA reduced triacylglycerol (TAG) accretion in the liver and extrahepatic tissues, while also attenuating inflammation and metabolic comorbidities. These effects were associated with modifications in the hepatic fatty acid profile, leading to reduced de novo lipogenesis and/or enhanced hepatic β-oxidation, depending on the specific FL combination. Furthermore, improvements in membrane properties, glucose metabolism, antioxidant and anti-inflammatory status, and cholesterol homeostasis contributed to the pleiotropic beneficial effects of FL combinations in MASLD.

The combination of TP with either n-3 PUFA or CLA reduced triacylglycerol (TAG) accretion in the liver and extrahepatic tissues, while also attenuating inflammation and metabolic comorbidities. These effects were associated with modifications in the hepatic fatty acid profile, leading to reduced de novo lipogenesis and/or enhanced hepatic β-oxidation, depending on the specific FL combination. Furthermore, improvements in membrane properties, glucose metabolism, antioxidant and anti-inflammatory status, and cholesterol homeostasis contributed to the pleiotropic beneficial effects of FL combinations in MASLD.

Conclusion

These findings indicate that combining bioactive fatty acids, such as n-3 PUFAs or CLA, with antioxidant FL may represent an effective strategy to synergistically reduce hepatic and extrahepatic lipid accretion and improve MASLD-associated metabolic dysfunction. Although the inherent limitations of animal studies should be considered, these results provide a promising basis for developing nutritional strategies aimed at preventing MASLD and other non-communicable chronic diseases.

These findings indicate that combining bioactive fatty acids, such as n-3 PUFAs or CLA, with antioxidant FL may represent an effective strategy to synergistically reduce hepatic and extrahepatic lipid accretion and improve MASLD-associated metabolic dysfunction. Although the inherent limitations of animal studies should be considered, these results provide a promising basis for developing nutritional strategies aimed at preventing MASLD and other non-communicable chronic diseases.