Lipid droplets are intracellular mechanical stressors that impair hepatocyte function

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.

SIV Infection Is Associated with Transient Acute-Phase Steatosis in Hepatocytes In Vivo

“…CCR5 may also be expressed on hepatic stellate cells, and triggering of the stellate cells through this receptor may also result indirectly in hepatocyte damage [ 37 ]. Steatosis has also been shown to directly impair hepatocyte function [ 38 ], and the presence of the microvesicular form of steatosis in the macaques further points to hepatocyte damage during the acute SIV infection period. Unlike macrovesicular steatosis in which the hepatocyte is filled with a single large fat droplet that displaces the nucleus, microvesicular steatosis is caused by severe dysfunction of the mitochondrial beta-oxidation pathway and characterized by the presence of many small fat droplets that leave the nucleus in place and give the cytoplasm a foamy appearance [ 23 ].…”

Untitled

“…75 In vitro, large LDs can also distort hepatocyte nuclei and chromatin structure. 76 In preclinical rodent models, LD-laden hepatocytes compress the space of Disse, the subendothelial space that lies between the liver sinusoidal endothelial cells and hepatocytes. Under normal conditions, this region regulates blood flow (70% portal vein and 30% hepatic artery).…”

Promoting In Vivo NIR-II Fluorescent Imaging for Lipid in Lipid Metabolism Diseases Diagnosis

“…Holding the potential of exacerbating themselves into severe cases including cirrhosis and hepatocellular carcinoma (HCC), fatty liver diseases have evolved into a serious threat worldwide along with the development of productivity and particular attention to public health. , Distinguished from the malignant liver diseases, fatty liver diseases and the correlated lipid-caused disorders such as atherosclerosis (AS) were reported to be reversible at the early stage, while the typical management approaches were rationalizing the diet and conducting the physical exercise. , Similar to AS, which is mainly induced by the accumulation of lipid in arterial vessels accompanied by sophisticated factors, fatty liver diseases also exhibited the emblematic pathological characteristic of the undue fat accumulation as in lipid within hepatocytes from the clinical perspective. − Notably, lipid is more than the cellular energy depository. It suggests depth participation in a variety of physiological and pathological events including lipid metabolism, membrane dynamics, and corresponding signal transduction. − Based on the tight association with fatty liver diseases and AS, lipid in overexpression and overexpansion can be considered as potential targets for both diagnosis and therapeutical methods .…”