Dietary cholesterol exacerbates hepatic steatosis and inflammation in obese LDL receptor-deficient mice

Subramanian, Savitha; Goodspeed, Leela; Wang, Shari A.; Kim, Jinkyu; Zeng, Lixia; Ioannou, George N.; Haigh, W. Geoffrey; Yeh, Matthew M.; Kowdley, Kris V.; O’Brien, Kevin D.; Pennathur, Subramaniam; Chait, Alan

doi:10.1194/jlr.m016246

Cited by 210 publications

(188 citation statements)

References 49 publications

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“…Recent experimental studies suggest that FC is an important lipotoxic molecule that promotes the development of NASH (3)(4)(5)(6)(7)(8)(9)(10)(11)(12). Thus, using diverse animal models [dietary with cholesterolcontaining atherogenic (Ath) diets ( 4,5,7 ), LDLR knockout and ApoE knock-in mice ( 9-12 ), appetite-defective Alms1 mutant ( foz/foz ) ( 6,8 ), or melanocortin 4 receptor-defi cient ( Mc4r-ko ) ( 13 ) mice fed an Ath diet, and ABCB4 mutant opossums with defective hepatic cholesterol excretion in bile ( 14 )], there is support for a consistent association between hepatic FC content and NASH pathology.…”

Section: Assessment Of Kc Crown-like Structures and Activation Of Thementioning

confidence: 99%

Cholesterol-lowering drugs cause dissolution of cholesterol crystals and disperse Kupffer cell crown-like structures during resolution of NASH

Ioannou

Rooyen

Savard

et al. 2015

Journal of Lipid Research

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Nonalcoholic fatty liver disease (NAFLD) is characterized by increased lipid deposition within hepatocytes attributable to metabolic causes in the absence of viral hepatitis or liver disorders caused by excessive alcohol or toxic drug consumption or other liver disorders. In the majority of patients, NAFLD manifests histologically as "simple steatosis" defi ned as hepatic steatosis without substantial infl ammation or fi brosis. Simple steatosis carries a very low risk of progression to cirrhosis and liver dysfunction ( 1 ). However, 10-30% of patients with NAFLD have or develop nonalcoholic steatohepatitis (NASH), characterized by hepatic lobular infl ammation and fi brosis in addition to steatosis. Progression to cirrhosis occurs in a proportion of patients ( 1, 2 ). The factor(s) responsible for the development of progressive NASH, as opposed to simple steatosis, remain unclear. A prominent concept that has been invoked to explain the development of NASH is that of lipotoxicity. Hepatic lipotoxicity implies that exposure to, or accumulation of, certain lipid species within hepatic cells may directly cause cellular toxicity or act in a proinfl ammatory or profi brotic manner. According to the hypothesis of hepatic lipotoxicity, NASH develops when the liver is exposed to lipotoxic lipid species, whereas simple steatosis develops in response to over-nutrition when the liver is not signifi cantly exposed to lipotoxic lipid species. It is generally accepted that triglycerides, which constitute the majority of hepatic lipids in NASH and simple steatosis, are a "safe" storage lipid with little or no lipotoxic potential. Relatively small quantities of other lipotoxic lipid species may exert a disproportionate impact in the development of NASH.Lipidomic analyses of human livers with NAFLD reported that levels of free (unesterifi ed) cholesterol (FC) were increased in NASH but not in simple steatosis, whereas levels of Abstract Cholesterol crystals form within hepatocyte lipid droplets in human and experimental nonalcoholic steatohepatitis (NASH) and are the focus of crown-like structures (CLSs) of activated Kupffer cells (KCs). Obese, diabetic

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Section: Assessment Of Kc Crown-like Structures and Activation Of Thementioning

confidence: 99%

Cholesterol-lowering drugs cause dissolution of cholesterol crystals and disperse Kupffer cell crown-like structures during resolution of NASH

Ioannou

Rooyen

Savard

et al. 2015

Journal of Lipid Research

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“…Ldlr Ϫ / Ϫ mice, or those fed with diets high in cholesterol, exhibit accumulation of hepatic lipids ( 76,77 ). To determine whether this was also true in zebrafi sh, we stained ldlr morphants using ORO.…”

Section: Increased Liver Lipid Accumulation and Hepatomegaly In Ldlr mentioning

confidence: 99%

Disruption of ldlr causes increased LDL-c and vascular lipid accumulation in a zebrafish model of hypercholesterolemia

O’Hare

Wang

Montasser

et al. 2014

Journal of Lipid Research

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Hypercholesterolemia is a primary cause of atherosclerosis and subsequent cardiovascular events. Genetic factors play a major role in regulation of plasma cholesterol levels, with heritability estimated to range from 40 to 70% [reviewed in ( 1 )]. Over 100 genomic regions have been associated with changes in plasma lipid levels ( 2-5 ). Despite the large number of putative candidate genes identifi ed, the functions of many remain largely unknown, owing in part to the lack of physiologically relevant in vivo models with which to validate and characterize the functionality of associated variants ( 3, 4, 6-13 ). Development of novel models in which genes can be individually targeted will likely reveal functional roles for genetic determinants of blood lipid levels and may facilitate discovery of novel targets for drug development.The zebrafi sh is an excellent candidate for establishing genetic models of hyperlipidemia due to conservation of cell types and molecular pathways involved in lipid metabolism and cholesterol synthesis ( 8,(14)(15)(16)(17)(18)(19)(20). These include hepatocytes, adipocytes, and pancreatic acinar cells ( 17 ) as well as expression of genes involved in lipid transport and metabolism, such as LDL receptor ( ldlr ), sterol regulatory element binding protein ( srebp ) 1/2 , and HMG-CoA reductase ( Hmgcr ) ( 18-29 ). Consequently, mechanisms of lipid metabolism, storage, absorption, and transport are highly conserved in zebrafi sh, allowing for physiologically relevant investigation of these processes ( 20,28,(30)(31)(32)(33)(34). Moreover, targeted suppression of gene expression can be easily achieved in zebrafi sh embryos, making assessment of the resulting larval phenotypes feasible for a large number

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“…Alanine aminotransferase (ALT) was measured using an autoanalyzer through the Nutrition and Obesity Research Center at the University of Washington. Tissue and fecal lipids were extracted using the Folch technique ( 13,14 ). Intra-peritoneal glucose and insulin tolerance tests were performed after a 4 h fast as described previously ( 6 ).…”

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confidence: 99%

Inhibition of intestinal cholesterol absorption decreases atherosclerosis but not adipose tissue inflammation

Umemoto

Subramanian

Ding

et al. 2012

Journal of Lipid Research

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Dietary cholesterol exacerbates hepatic steatosis and inflammation in obese LDL receptor-deficient mice

Cited by 210 publications

References 49 publications

Cholesterol-lowering drugs cause dissolution of cholesterol crystals and disperse Kupffer cell crown-like structures during resolution of NASH

Cholesterol-lowering drugs cause dissolution of cholesterol crystals and disperse Kupffer cell crown-like structures during resolution of NASH

Disruption of ldlr causes increased LDL-c and vascular lipid accumulation in a zebrafish model of hypercholesterolemia

Inhibition of intestinal cholesterol absorption decreases atherosclerosis but not adipose tissue inflammation

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