Lipid droplets are intracellular mechanical stressors that impair hepatocyte function

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 120; no. 16; p. e2216811120
• Main Authors: Loneker, Abigail E., Alisafaei, Farid, Kant, Aayush, Li, David, Janmey, Paul A., Shenoy, Vivek B., Wells, Rebecca G.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 18.04.2023
• Subjects: Biological Sciences; Cancer; Carcinoma, Hepatocellular - pathology; Chromatin; Cirrhosis; Deformation effects; Droplets; Fatty acids; Fatty liver; Hepatocellular carcinoma; Hepatocytes; Hepatocytes - pathology; Humans; Inclusions; Intracellular; Lipid Droplets - metabolism; Lipid Metabolism - physiology; Lipids; Liver; Liver diseases; Liver Neoplasms - pathology; Mathematical analysis; Mathematical models; Mechanical stimuli; Non-alcoholic Fatty Liver Disease - pathology; Nuclear deformation; Physical Sciences; Risk factors; Soft tissues; Stiffening; Stiffness; mechanobiology; nuclear deformation; chromatin condensation; cytoskeleton; HNF4α
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2216811120

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.