Lipid droplets are intracellular mechanical stressors that impair hepatocyte function

Abigail E. Loneker, Farid Alisafaei, Aayush Kant, David Li, Paul A. Janmey, Vivek B. Shenoy, Rebecca G. Wells

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Matrix stiffening and external mechanical stress have been linked to disease and cancer development in multiple tissues, including the liver, where cirrhosis (which increases stiffness markedly) is the major risk factor for hepatocellular carcinoma. Patients with nonalcoholic fatty liver disease and lipid droplet-filled hepatocytes, however, can develop cancer in noncirrhotic, relatively soft tissue. Here, by treating primary human hepatocytes with the monounsaturated fatty acid oleate, we show that lipid droplets are intracellular mechanical stressors with similar effects to tissue stiffening, including nuclear deformation, chromatin condensation, and impaired hepatocyte function. Mathematical modeling of lipid droplets as inclusions that have only mechanical interactions with other cellular components generated results consistent with our experiments. These data show that lipid droplets are intracellular sources of mechanical stress and suggest that nuclear membrane tension integrates cell responses to combined internal and external stresses.

Original languageEnglish (US)
Article numbere2216811120
JournalProceedings of the National Academy of Sciences of the United States of America
Volume120
Issue number16
DOIs
StatePublished - Apr 18 2023

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • HNF4α
  • chromatin condensation
  • cytoskeleton
  • mechanobiology
  • nuclear deformation

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