Molecular Mechanisms and Therapeutic Targets in Steatosis and Steatohepatitis

Anderson, Nora; Borlak, Jürgen

doi:10.1124/pr.108.00001

Cited by 342 publications

(273 citation statements)

References 744 publications

(852 reference statements)

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“…The fat droplet forms in or alongside the ER in conjunction with apolipoprotein B and adipophilin [35][36][37]. The droplet serves as a means of safely storing fatty acids as triglyceride or exporting them through lipid transfer from the droplet to nascent very-low-density lipoproteins.…”

Section: Fat Dropletsmentioning

confidence: 99%

Ultrastructural findings in human nonalcoholic steatohepatitis

Jayakumar

Guillot

Argo

et al. 2011

Expert Review of Gastroenterology & Hepatology

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Section: Fat Dropletsmentioning

confidence: 99%

Ultrastructural findings in human nonalcoholic steatohepatitis

Jayakumar

Guillot

Argo

et al. 2011

Expert Review of Gastroenterology & Hepatology

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“…inflammation (such as tumour-necrosis factor-a or interleukin 6), oxidative stress (such as catalase, glutathione peroxidase and overall plasma ferric reducing ability), apoptosis and fibrosis have also been proposed as biomarkers for staging NAFLD 29,30 . Among these, the apoptosis markers are arguably the ones with the best predictive ability.…”

mentioning

confidence: 99%

Genome-scale metabolic modelling of hepatocytes reveals serine deficiency in patients with non-alcoholic fatty liver disease

et al. 2014

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Several liver disorders result from perturbations in the metabolism of hepatocytes, and their underlying mechanisms can be outlined through the use of genome-scale metabolic models (GEMs). Here we reconstruct a consensus GEM for hepatocytes, which we call iHepatocytes2322, that extends previous models by including an extensive description of lipid metabolism. We build iHepatocytes2322 using Human Metabolic Reaction 2.0 database and proteomics data in Human Protein Atlas, which experimentally validates the incorporated reactions. The reconstruction process enables improved annotation of the proteomics data using the network centric view of iHepatocytes2322. We then use iHepatocytes2322 to analyse transcriptomics data obtained from patients with non-alcoholic fatty liver disease. We show that blood concentrations of chondroitin and heparan sulphates are suitable for diagnosing non-alcoholic steatohepatitis and for the staging of non-alcoholic fatty liver disease. Furthermore, we observe serine deficiency in patients with NASH and identify PSPH, SHMT1 and BCAT1 as potential therapeutic targets for the treatment of non-alcoholic steatohepatitis.

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“…These mechanisms have been proposed as causal explanations for hepatic steatosis associated with nonalcoholic fatty liver disease. [1][2][3][4] The endoplasmic reticulum (ER) is an essential organelle in lipid metabolism. First, VLDL generation depends on a functional ER.…”

mentioning

confidence: 99%

A protective role for CD154 in hepatic steatosis in mice

et al. 2010

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Inflammation and lipid metabolism pathways are linked, and deregulation of this interface may be critical in hepatic steatosis. The importance of the dialog between inflammatory signaling pathways and the unfolded protein response (UPR) in metabolism has been underlined. Herein, we studied the role of CD154, a key mediator of inflammation, in hepatic steatosis. To this end, Balb/c mice, wild-type or deficient in CD154 (CD154KO), were fed a diet rich in olive oil. In vitro, the effect of CD154 was studied on primary hepatocyte cultures and hepatocyte-derived cell lines. Results showed that CD154KO mice fed a diet rich in olive oil developed hepatic steatosis associated with reduced apolipoprotein B100 (apoB100) expression and decreased secretion of very low-density lipoproteins. This phenotype correlated with an altered UPR as assessed by reduced X-Box binding protein-1 (XBP1) messenger RNA (mRNA) splicing and reduced phosphorylation of eukaryotic initiation factor 2a. Altered UPR signaling in livers of CD154KO mice was confirmed in tunicamycin (TM) challenge experiments. Treatment of primary hepatocyte cultures and hepatocyte-derived cell lines with soluble CD154 increased XBP1 mRNA splicing in cells subjected to either oleic acid (OA) or TM treatment. Moreover, CD154 reduced the inhibition of apoB100 secretion by HepG2 cells grown in the presence of high concentrations of OA, an effect suppressed by XBP1 mRNA silencing and in HepG2 cells expressing a dominant negative form of inositol requiring ER-to-nucleus signaling protein-1. The control of the UPR by CD154 may represent one of the mechanisms involved in the pathophysiology of hepatic steatosis. Conclusion: Our study identifies CD154 as a new mediator of hepatic steatosis. (HEPATOLOGY 2010;52:1968-1979

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Molecular Mechanisms and Therapeutic Targets in Steatosis and Steatohepatitis

Cited by 342 publications

References 744 publications

Ultrastructural findings in human nonalcoholic steatohepatitis

Ultrastructural findings in human nonalcoholic steatohepatitis

Genome-scale metabolic modelling of hepatocytes reveals serine deficiency in patients with non-alcoholic fatty liver disease

A protective role for CD154 in hepatic steatosis in mice

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