Biology subjects

Sack, I.

Publications and source records attributed to Sack, I..

4 recordsLinked to original sources

bioRxiv2025

Liver Viscosity Decreases Before the Onset of Fibrosis in Metabolic Dysfunction-Associated 1 Steatohepatitis (MASH)

Background and AimMetabolic dysfunction-associated steatohepatitis (MASH) is an increasingly prevalent condition worldwide, associated with biomechanical liver changes and detectable by magnetic resonance elastography (MRE). This study explored the pathophysiological features and their biomechanical manifestations at different stages of MASH in a mouse dietary model. MethodsUsing MRE on a clinical 3 Tesla MRI scanner, we measured liver stiffness, viscosity, fat fraction and water diffusion in 45 male mice. These values were correlated with histopathology and proteomics analyses to further characterize the liver microstructural and metabolic changes during MASH progression. ResultsWe found in a high-fat, low amino-acid model that early MASH was marked by fat accumulation and increasing inflammatory activity, while later stages showed a reduction in fat despite persistent inflammation. These changes in microstructure were associated with biomechanical adaptations, including a progressive decrease in hepatic viscosity and the water diffusion. Notably, viscosity was inversely correlated with lobular inflammation, cell adhesion, antioxidant activity, and metabolic adaptations such as enhanced ketone body synthesis. These findings, which precede the onset of fibrosis and tissue stiffening, show that tissue viscosity is highly sensitive to early microstructural and metabolic alterations in MASH. ConclusionSteatosis and inflammation significantly alter liver biophysical properties, particularly viscosity, in a mouse dietary model of MASH, even in the absence of fibrosis. These findings suggest that viscosity is a potential early and clinically translatable biomarker for the development and progression of MASH.

biophysics↗

bioRxiv2025

Longitudinal in vivo MR elastography reveals whole-liver viscoelastic involvement in a murine model of hepatocellular carcinoma

Cancer cells actively shape their microenvironment and adapt the physical and biomechanical properties of the host tissue. However, for organs like the liver, especially in vivo, it remains unclear at what rate and spatial extent macroscopic viscoelastic properties change during formation of a cancer-permissive environment. Using clinical multifrequency magnetic resonance elastography (MRE) in a mouse model of hepatocellular carcinoma (HCC), we identified surprisingly early and large-scale viscoelasticity changes leading to whole-liver biomechanical involvement stretching far beyond the local cancer microenvironment. Widespread liver softening began two weeks after HCC inoculation, followed by a decrease in tissue viscosity and fluidity two weeks later, preceding any macroscopic evidence of local tumor growth. In contrast, local lesions with stiff-rigid biomechanical properties were not detectable by standard MRI and MRE until five to six weeks post-injection. Furthermore, tumor viscoelasticity correlated with that of the host liver, also suggesting a possible widespread adaptation of the biomechanical properties beyond the tumor margins and its local niche during early liver colonization. The observed large-scale viscoelastic signature, detectable just two weeks after tumor cells injection, could serve as a non-invasive imaging biomarker to inform physicians about tumor niche formation and liver cancer progression long before any macroscopic manifestation of solid tumors.

biophysics↗

bioRxiv2024

Intrahepatic crystals from elevated dietary cholesterol are sufficient to stiffen the liver

Chronic lipid accumulation is a hallmark of metabolic dysfunction-associated steatotic liver disease (MASLD), and dyslipidemia is associated with disease progression and poorer patient outcomes. Tissue stiffening is an established fibrogenic cue, but how changes in lipid accumulation affect tissue mechanics is not fully understood. Here we show that cholesterol-containing lipid crystals stiffen steatotic liver tissue. We show that rats fed elevated dietary cholesterol develop both liquid and solid cholesterol-containing lipid crystals in the liver. While steatotic livers without crystals are softer than control livers, livers with lipid crystals show increased baseline stiffness and compression stiffening as well as increased progression to fibrosis. Lipid extracts from livers containing crystals stiffen fibrous tissue mimics, while depletion of cholesterol using methyl--cyclodextrin reduces both crystal abundance and tissue stiffness. Our results demonstrate in a rat model that a high cholesterol diet leads to formation of liquid and solid crystals and that cholesterol-containing crystals stiffen tissues. This work implicates lipid crystals arising from dyslipidemia as a key driver of MASLD progression. The presence of cholesterol crystals could lead to new diagnostic tools for progressive MASLD and could be a therapeutic target.

physiology↗

bioRxiv2022

Adipose cells and tissues soften with lipid accumulation while in diabetes adipose tissue stiffens

Adipose tissue expansion involves both differentiation of new precursors and size increase of mature adipocytes. While the two processes are well balanced in healthy tissues, obesity and diabetes type II are associated with abnormally enlarged adipocytes and excess lipid accumulation. We hypothesised that adipocyte shape and size changes with differentiation and lipid accumulation would be accompanied by changes in the mechanical phenotype at both the cell and tissue level. We quantified by optical diffraction tomography (ODT) that differentiating preadipocytes increased their volumes drastically. Atomic force microscopy (AFM)-indentation and -microrheology revealed that during the early phase of differentiation, human preadipocytes became more compliant and more fluid-like, concomitant with ROCK-mediated F-actin remodelling. Adipocytes that had accumulated large lipid droplets were more compliant, and further promoting lipid accumulation led to an even more compliant phenotype. In line with that, high fat diet-induced obesity was associated with more compliant adipose tissue compared to lean animals, both for drosophila fat bodies and murine gonadal adipose tissue. In contrast, adipose tissue of diabetic mice became significantly stiffer as shown not only by AFM but also magnetic resonance elastography (MRE). Altogether, we dissect relative contributions of the cytoskeleton and lipid droplets to cell and tissue mechanical changes across different functional states, such as differentiation, nutritional state and disease. Since preadipocytes are mechanosensitive, tissue stiffening in diabetes might be critical to the balance between hyperplasia and hypertrophy and moreover present a potential target in the prevention of metabolic disorders.

biophysics↗