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Human Multilineage 3D Spheroids as a Model of Liver Steatosis and Fibrosis.

ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder in western countries. Despite the high prevalence of NAFLD, the underlying biology of the disease progression is not clear, and there are no approved drugs to treat non-alcoholic steatohepatitis (NASH), the most advanced form of the disease. Thus, there is an urgent need for developing advanced in vitro human cellular systems to study disease mechanisms and drug responses. We attempted to create an organoid system genetically predisposed to NAFLD and to induce steatosis and fibrosis in it by adding free fatty acids. We used multilineage 3D spheroids composed by hepatocytes (HepG2) and hepatic stellate cells (LX-2) with a physiological ratio (24:1). HepG2 and LX-2 cells are homozygotes for the PNPLA3 I148M sequence variant, the strongest genetic determinant of NAFLD. We demonstrate that hepatic stellate cells facilitate the compactness of 3D spheroids. Then, we show that the spheroids develop accumulations of fat and collagen upon exposure to free fatty acids. Finally, this accumulation was rescued by incubating spheroids with liraglutide or elafibranor, drugs that are in clinical trials for the treatment of NASH. In conclusion, we have established a simple, easy to handle, in vitro model of genetically induced NAFLD consisting of multilineage 3D spheroids. This tool may be used to understand molecular mechanisms involved in the early stages of fibrogenesis induced by lipid accumulation. Moreover, it may be used to identify new compounds to treat NASH using high-throughput drug screening.

SUBMITTER: Pingitore P

PROVIDER: S-EPMC6480107 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Human Multilineage 3D Spheroids as a Model of Liver Steatosis and Fibrosis.

Pingitore Piero P Sasidharan Kavitha K Ekstrand Matias M Prill Sebastian S Lindén Daniel D Romeo Stefano S

International journal of molecular sciences 20190402 7

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder in western countries. Despite the high prevalence of NAFLD, the underlying biology of the disease progression is not clear, and there are no approved drugs to treat non-alcoholic steatohepatitis (NASH), the most advanced form of the disease. Thus, there is an urgent need for developing advanced in vitro human cellular systems to study disease mechanisms and drug responses. We attempted to create an organoid system geneti ...[more]

PMID: 30986904

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Project description:IntroductionUltrasonography is widely used as the first tool to evaluate fatty liver disease, and the hepatorenal index is a semi-quantitative method that improves its performance. Fibrosis can co-exist with steatosis or even replace it during disease progression. This study aimed to evaluate the influence of fibrosis on the measurement of steatosis using the hepatorenal index.Materials and methodsThis cross-sectional study included 89 patients with nonalcoholic fatty liver disease and in whom liver fibrosis was determined by ultrasound elastography. The Pearson's correlation coefficient was used to compare between the results of the sonographic hepatorenal index and the quantification of steatosis using magnetic resonance spectroscopy as well the accuracy of detecting moderate to severe steatosis using sonography in two groups of patients: (A) without advanced fibrosis and (B) with advanced fibrosis. Advanced fibrosis was defined as a shear wave speed ≥ 1.78 m/s on ultrasound elastography. We calculated the area under the curve (AUC-ROC) to detect the ability of the hepatorenal index to differentiate light from moderate to severe steatosis in both groups. Moderate to severe steatosis was defined as a fat fraction > 15% on the magnetic resonance spectroscopy. The intra-observer variability was assessed using the Bland-Altman plot.ResultsAmong patients, the mean age was 54.6 years and 59.6% were women, 50.6% had a body mass index ≥ 30 kg/m2, 29.2% had moderate to severe steatosis, and 27.2% had advanced fibrosis. There was a correlation between steatosis grading by ultrasonography and magnetic resonance in group A (0.73; P < 0.001), but not in Group B (0.33; P = 0.058). The AUC-ROC for detecting a steatosis fraction ≥ 15% was 0.90 and 0.74 in group A and group B, respectively. The intra-observer variability for the hepatorenal index measurements was not significant (-0.036; P = 0.242).ConclusionThe hepatorenal index is not appropriate for estimating steatosis in livers with advanced fibrosis.

Dataset Information

Human Multilineage 3D Spheroids as a Model of Liver Steatosis and Fibrosis.

Publications

Human Multilineage 3D Spheroids as a Model of Liver Steatosis and Fibrosis.

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