Mechanisms of Lipid Droplet Accumulation in Steatotic Liver Diseases

Abstract

The steatotic diseases of non-alcoholic fatty liver disease, alcohol-associated liver disease and chronic Hepatitis C account for the majority of liver disease prevalence, morbidity and mortality worldwide. While these diseases have distinct pathogenic and clinical features, dysregulated lipid droplet (LD) organelle biology represents a convergence of pathogenesis in all three. With increasing understanding of hepatocyte LD biology, we now understand the roles of LD proteins involved in these diseases but also how genetics modulate LD biology to either exacerbate or protect against the phenotypes associated with steatotic liver diseases. Here, we review the history of the LD organelle and its biogenesis and catabolism. We also review how this organelle is critical not only for the steatotic phenotype of liver diseases but also for their advanced phenotypes. Finally, we summarize the latest attempts and challenges of leveraging LD biology for therapeutic gain in steatotic diseases. In conclusion, the study of dysregulated LD biology may lead to novel therapeutics for the prevention of disease progression in the highly prevalent steatotic liver diseases of MASLD, ALD and HCV.

Silencing of Hepatic AATF Ameliorates Metabolic Dysfunction Associated Steatohepatitis by Promoting Fatty Acid β-Oxidation in Experimental models

“…Beta-oxidation of fatty acids is intricately linked to the pathogenesis of MASH. Dysregulation of beta-oxidation pathways contributes to hepatic lipid accumulation, oxidative stress, and inflammation, driving the progression of the disease (32). Along similar lines, our studies revealed the upregulation of metabolites involved in mitochondrial beta-oxidation pathway alongside the biosynthesis of phosphatidylcholine (PC) in WD siAATF through pathway enrichment analysis using the SMPB database ( Figure 9A ).…”

A triphenylamine-based fluorescent probe with large Stokes shift for wash-free imaging of lipid droplets and diagnosis of fatty liver

“…Recently, extensive research has revealed that excessive accumulation of fat in hepatocyte lipid droplets (LDs) is a prominent pathological characteristic of NAFLD lesions. 8,9 LDs are spherical organelles composed of phospholipid membranes and neutral lipids, which play an irreplaceable role in lipid synthesis and metabolism, protein degradation, maintenance of cellular energy homeostasis, and other crucial processes. 10–12 Dysregulation of their functions may contribute to liver steatosis, type II diabetes, and atherosclerosis.…”

The lipid droplet lipidome

“…While in prokaryotes, LDs (or PHA granules) are believed to serve purely as energy storage units formed in response to nutrient deprivation [1,2], in eukaryotes LDs have evolved into multifunctional organelles acting as a fuse at the crossroads of multiple metabolic pathways [3]. With the development of new methodologies to manipulate (genetics, biochemistry), visualize (fluorescent microscopy, electron microscopy), and access molecular composition (Raman and nuclear magnetic resonance spectroscopy, mass spectrometry) of LDs, our current knowledge of their biology has grown enormously over recent decades [3][4][5]. The current understanding of LD biology identifies them as a central hub in lipid metabolism and trafficking, capable of orchestrating intra-and extra-cellular lipid fluxes.…”

“…Among pathophysiological conditions associated with extensive LD formation are adipocyte hypertrophy in obesity [4], liver [5] and pancreatic steatosis [6], neurodegeneration [7], cardiovascular diseases [8], infections [9], and cancer [10]. At the mechanistic level, in addition to the storage and release of energy in the form of fatty acyl equivalents, LD biogenesis is closely linked to the cellular stress responses.…”