Abstract
The liver is the key organ involved in lipid metabolism and transport. Excessive lipid accumulation due to dysregulated lipid metabolism predisposes the liver to steatosis, cirrhosis, and hepatocellular carcinoma. Lipids are generally compartmentalized in specialized organelles called lipid droplets that enable cells to store and release lipids in a regulated manner. However, during flux-in and flux-out of droplets, lipids are converted into toxic species leading to lipid-mediated liver damage. Lipids are categorized into 'toxic' or 'healthy' lipids that are involved in liver disease pathogenesis or resolution, respectively. Lipidomic analysis have revealed unique lipid signature that correlates with the disease progression therefore being used for disease diagnosis. In this comprehensive review, we provide an overview on hepatic lipid homeostasis, lipid compartmentalization mechanisms and lipidomic profiles in different liver diseases. We further discuss promising therapeutics targeting the hepatic lipidome including pro-resolving lipids, liposomes, and small-molecule inhibitors for the treatment of liver diseases.
Highlights
The liver plays a major role in metabolic homeostasis as it is responsible for the synthesis, storage, and redistribution of different biomolecules like lipids, proteins, and carbohydrates
Underlying mechanisms involved in lipophagy are still unknown, recent research reported the interaction between two GTPases - dynamin 2 (Dyn 2) and small regulatory Rab GTPase (Rab10) - that seem to induce synergistic effects important for accumulating and catabolizing lipid droplets (LDs) potentially linked to hepatocellular metabolism [33]
During cellular stress responses triggered by different factors, enzymes are upregulated that alter the oxidation of free fatty acids (FFAs) leading to the accumulation of saturated fatty acids (SFAs) and a decreased excretion of these products
Summary
The liver plays a major role in metabolic homeostasis as it is responsible for the synthesis, storage, and redistribution of different biomolecules like lipids, proteins, and carbohydrates. A dysregulated lipid metabolism/lipotoxicity can lead to liver diseases with different phenotypes and severities varying from mild steatosis, steatohepatitis, cirrhosis, and HCC. During steatosis, the LDassociated proteins are altered, leading to altered in- and out-flux of lipids from the LDs, which results in the conversion of lipids to socalled ‘toxic’ lipids These toxic lipids are unique molecular signatures that can be identified using lipidomic analysis and can be used as biomarkers for non-invasive diagnosis of a specific liver disease. We summarize the recent insights about the role of lipids in the development and progression of liver diseases of different etiologies and provide an overview of the lipids that can be used as biomarkers as well as therapeutics. We provide an outlook into the therapies that have been developed to remodel abnormal hepatic lipidome and to maintain lipid homeostasis
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