Hepatic lipid droplets: A balancing act between energy storage and metabolic dysfunction in NAFLD

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Abstract

Background: Non-alcoholic fatty liver disease (NAFLD) is defined by the abundance of lipid droplets (LDs) in hepatocytes. While historically considered simply depots for energy storage, LDs are increasingly recognized to impact a wide range of biological processes that influence cellular metabolism, signaling, and function. While progress has been made toward understanding the factors leading to LD accumulation (i.e. steatosis) and its progression to advanced stages of NAFLD and/or systemic metabolic dysfunction, much remains to be resolved. Scope of review: This review covers many facets of LD biology. We provide a brief overview of the major pathways of lipid accretion and degradation that contribute to steatosis and how they are altered in NAFLD. The major focus is on the relationship between LDs and cell function and the detailed mechanisms that couple or uncouple steatosis from the severity and progression of NAFLD and systemic comorbidities. The importance of specific lipids and proteins within or on LDs as key components that determine whether LD accumulation is linked to cellular and metabolic dysfunction is presented. We discuss emerging areas of LD biology and future research directions that are needed to advance our understanding of the role of LDs in NAFLD etiology. Major conclusions: Impairments in LD breakdown appear to contribute to disease progression, but inefficient incorporation of fatty acids (FAs) into LD-containing triacylglycerol (TAG) and the consequential changes in FA partitioning also affect NAFLD etiology. Increased LD abundance in hepatocytes does not necessarily equate to cellular dysfunction. While LD accumulation is the prerequisite step for most NAFLD cases, the protein and lipid composition of LDs are critical factors in determining the progression from simple steatosis. Further defining the detailed molecular mechanisms linking LDs to metabolic dysfunction is important for designing effective therapeutic approaches targeting NAFLD and its comorbidities.

Original languageEnglish (US)
Article number101115
JournalMolecular Metabolism
Volume50
DOIs
StatePublished - Aug 2021

Bibliographical note

Funding Information:
The author thanks Brian Finck, Sudha Biddinger, Lisa Chow, and members of the Mashek laboratory for their critical evaluation of this review. DGM is supported by NIH grants R01AG055452 and R01DK114401 .

Publisher Copyright:
© 2020 The Author

Keywords

  • Lipid droplets
  • Lipotoxicity
  • NAFLD
  • NASH
  • Perilipins

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