Hepatic cholesterol crystals and crown-like structures distinguish NASH from simple steatosis

Ioannou, George N.; Haigh, W. Geoffrey; Thorning, David; Savard, Christopher E.

doi:10.1194/jlr.m034876

Cited by 203 publications

(220 citation statements)

References 27 publications

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“…A morphometric study of liver biopsies demonstrated cholesterol crystals in lipid droplets in patients with steatohepatitis but not steatosis 199 . Statin use is safe in patients with liver disease 200 and a Cochrane review concluded that statins can improve steatosis and reduce aminotransferase levels but treatment trials with histological endpoints are lacking 201 .…”

Section: [H2] Reducing Injurymentioning

confidence: 96%

Nonalcoholic Fatty Liver Disease

Rinella

2015

JAMA

1,964

1,621

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Section: [H2] Reducing Injurymentioning

confidence: 96%

Nonalcoholic Fatty Liver Disease

Rinella

2015

JAMA

1,964

1,621

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“…The fatty acid composition and the accumulation of free cholesterol have been implicated in playing a critical role in the development of NASH since an altered lipidome [3,11,12] as well as free cholesterol, positively correlate with the severity of NASH [10,12,28,29] . Dietary cholesterol may play a role in NAFLD onset [30] .…”

Section: Discussionmentioning

confidence: 99%

“…Recent observations also highlighted the accumulation of free cholesterol as an important trigger for the progression from simple steatosis to severe NASH [9][10][11] . In fact, dietary cholesterol was demonstrated to be a critical factor in the progression of NASH [10,12] . Cholesterol fed to LDLR -/-mice induced a prominent inflammatory response, whereas high fat feeding without cholesterol induced steatosis in the absence of inflammation [13] .…”

Section: Introductionmentioning

confidence: 99%

Elevated free cholesterol in a p62 overexpression model of non-alcoholic steatohepatitis

Simon

Kessler

Gemperlein

et al. 2014

WJG

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AIM:To characterize how insulin-like growth factor 2 (IGF2 ) mRNA binding protein p62/IMP2-2 promotes steatohepatitis in the absence of dietary cholesterol. METHODS:Non-alcoholic steatohepatitis (NASH) was induced in wild-type mice and in mice overexpressing p62 specifically in the liver by feeding the mice a methionine and choline deficient (MCD) diet for either two or four weeks. As a control, animals were fed a methionine and choline supplemented diet. Serum triglycerides, cholesterol, glucose, aspartate aminotransferase and alanine transaminase were determined by standard analytical techniques. Hepatic gene expression was determined by real-time reverse transcription-polymerase chain reaction. Generation of reactive oxygen species in liver tissue was quantified as thiobarbituric acid reactive substances using a photometric assay and malondialdehyde as a standard. Tissue fatty acid profiles and cholesterol levels were analyzed by gas chromatographymass spectrometry after hydrolysis. Hepatocellular iron accumulation was determined by Prussian blue staining in paraffin-embedded formalin-fixed tissue. Filipin staining on frozen liver tissue was used to quantify hepatic free cholesterol levels. Additionally, nuclear localization of the nuclear factor kappa B (NF-κB) subunit p65 was examined in frozen tissues. RESULTS:Liver-specific overexpression of the insulin-like growth factor 2 mRNA binding protein 2-2 (IGF2BP2-2/IMP2-2/p62) induces steatosis with regular chow and amplifies NASH-induced fibrosis in the MCD mouse model. Activation of NF-κB and expression of NF-κB target genes suggested an increased inflammatory response in p62 transgenic animals. Analysis of hepatic lipid composition revealed an elevation of monounsaturated fatty acids as well as increased hepatic cholesterol. Moreover, serum cholesterol was significantly elevated in p62 transgenic mice. Dietary cholesterol represents a critical factor for the development of NASH from hepatic steatosis. Filipin staining revealed increased free cholesterol in p62 transgenic livers, which were not diet-derived. The mRNA levels of the rate-limiting enzyme for cholesterol synthesis 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase or HMGCR) were not significantly upregulated, potentially due to increased cholesterol biosynthesis via elevated sterol regulatory element binding transcription factor 2 (SREBF2 ) gene expression and increased iron deposition in transgenic animals. CONCLUSION:This study provides evidence that p62/IGF2BP2-2 drives the progression of NASH through elevation of hepatic iron deposition and increased production of hepatic free cholesterol.

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“…What is less clear is how liver macrophages behave during the disease progression particularly in relation with the development of fibrosis (Tacke and Zimmermann, 2014). Recent studies have pointed out that hepatic macrophages in human NASH, but not in patients with simple steatosis often cluster around lipid droplets derived from death hepatocytes forming crown-like aggregates similar to those present in the inflamed visceral adipose tissue of obese patients (Rensen et al, 2009, Caballero et al, 2012and Ioannou et al, 2013. Furthermore, these macrophages appear enlarged and contained lipid vesicles and cholesterol crystals resembling foam cells of atherosclerotic plaques (Ioannou et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

“…Recent studies have pointed out that hepatic macrophages in human NASH, but not in patients with simple steatosis often cluster around lipid droplets derived from death hepatocytes forming crown-like aggregates similar to those present in the inflamed visceral adipose tissue of obese patients (Rensen et al, 2009, Caballero et al, 2012and Ioannou et al, 2013. Furthermore, these macrophages appear enlarged and contained lipid vesicles and cholesterol crystals resembling foam cells of atherosclerotic plaques (Ioannou et al, 2013). Interestingly, clusters of foamy macrophages are also evident in several mice models of experimental NASH in association with lobular inflammation and hepatic fibrosis (Itoh et al, 2013 andIoannou et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Fat-laden macrophages modulate lobular inflammation in nonalcoholic steatohepatitis (NASH)

Jindal

Bruzzì

Sutti

et al. 2015

Experimental and Molecular Pathology

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Highlights• Liver macrophages have an important role in promoting hepatic inflammation in nonalcoholic steatohepatitis (NASH) • In both mice and human NASH liver macrophages are enlarged and contain lipid vesicles • Despite inflammatory features, enlarged macrophages in NASH show an increased production of anti-inflammatory mediators • Enlarged macrophage accumulation in NASH may influence hepatic inflammatory responses AbstractNonalcoholic steatohepatitis (NASH) is characterized by extensive hepatic monocyte infiltration and monocyte-derived macrophages have an important role in regulating the disease evolution. However, little is known about the functional changes occurring in liver macrophages during NASH progression. In this study, we investigated phenotypic and functional modifications of hepatic macrophages in experimental NASH induced by feeding C57BL/6 mice with a methionine-choline deficient (MCD) diet up to 8 weeks.In mice with steatohepatitis liver F4/80-positive macrophages increased in parallel with the disease progression and formed small clusters of enlarged and vacuolated cells. At immunofluorescence these cells contained lipid vesicles positive for the apoptotic cell marker Annexin V suggesting the phagocytosis of apoptotic bodies derived from dead fat-laden hepatocytes. Flow cytometry revealed that these enlarged macrophages expressed inflammatory monocyte (CD11b, Ly6C, TNF-α) markers. However, as compared to regular size macrophages the enlarged sub-set was characterized by an enhanced production of arginase-1 and of the anti-inflammatory mediators IL-10 and annexin A1. Similar vacuolated macrophages producing annexin A1 were also evident in liver biopsies of NASH patients. In mice with NASH, the accumulation of enlarged F4/80 + cells paralleled with a decline in the expression of the macrophage M1 activation markers iNOS, IL-12 and CXCL10, while the levels of M2 polarization markers arginase-1 and MGL-1 were unchanged. Interestingly, the lowering of IL-12 expression mainly involved the macrophage sub-set with regular size.We conclude that during the progression of NASH fat accumulation within liver macrophages promotes the production of anti-inflammatory mediators that influence hepatic inflammatory responses. Abbreviations NAFLD, nonalcoholic fatty liver disease;  NASH, nonalcoholic steatohepatitis;  MCD, methionine-choline deficient diet;  (iNOS), inducible NO synthase;  (AnxA1), annexin A1

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Hepatic cholesterol crystals and crown-like structures distinguish NASH from simple steatosis

Cited by 203 publications

References 27 publications

Nonalcoholic Fatty Liver Disease

Nonalcoholic Fatty Liver Disease

Elevated free cholesterol in a p62 overexpression model of non-alcoholic steatohepatitis

Fat-laden macrophages modulate lobular inflammation in nonalcoholic steatohepatitis (NASH)

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