Nonalcoholic fatty liver disease severity is associated with the ratios of total cholesterol and triglycerides to high-density lipoprotein cholesterol

Wu, Kuan-Ta; Kuo, Po‐Lin; Su, Shih‐Bin; Chen, Yiyu; Yeh, M.H.; Huang, Ching‐I; Yang, Jeng‐Fu; Lin, Chia-I; Hsieh, Meng‐Hsuan; Hsieh, Ming‐Yen; Lin, Wen‐Yi; Yu, Ming‐Lung; Dai, Chia‐Yen; Wang, Hsien-Yi

doi:10.1016/j.jacl.2015.12.026

Cited by 91 publications

(74 citation statements)

References 35 publications

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“…The Rx-HDL group also had 20% lower hepatic cholesterol levels than the HDL group (P = 0.06) and 33.3% lower levels than the PBS group (P = 0.00043). A recent study suggested that high HDL levels are associated with a lower degree of steatosis, which might explain the reduced hepatic triglyceride and cholesterol levels in mice treated with vehicle HDL nanoparticles (31). Furthermore, GW3965 has been reported to increase HDL levels in mice (32), likely explaining the additional hepatic benefits in Rx-HDL-treated mice.…”

Section: Distinct Immune Cell Targeting Patterns Within the Nanoparticlementioning

confidence: 99%

Immune cell screening of a nanoparticle library improves atherosclerosis therapy

Tang

Baxter

Menon

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

106

124

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Immunological complexity in atherosclerosis warrants targeted treatment of specific inflammatory cells that aggravate the disease. With the initiation of large phase III trials investigating immunomodulatory drugs for atherosclerosis, cardiovascular disease treatment enters a new era. We here propose a radically different approach: implementing and evaluating in vivo a combinatorial library of nanoparticles with distinct physiochemical properties and differential immune cell specificities. The library's nanoparticles are based on endogenous high-density lipoprotein, which can preferentially deliver therapeutic compounds to pathological macrophages in atherosclerosis. Using the apolipoprotein E-deficient (Apoe −/− ) mouse model of atherosclerosis, we quantitatively evaluated the library's immune cell specificity by combining immunological techniques and in vivo positron emission tomography imaging. Based on this screen, we formulated a liver X receptor agonist (GW3965) and abolished its liver toxicity while still preserving its therapeutic function. Screening the immune cell specificity of nanoparticles can be used to develop tailored therapies for atherosclerosis and other inflammatory diseases.nanomedicine | drug delivery | immunotherapy | molecular imaging | atherosclerosis

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Section: Distinct Immune Cell Targeting Patterns Within the Nanoparticlementioning

confidence: 99%

Immune cell screening of a nanoparticle library improves atherosclerosis therapy

Tang

Baxter

Menon

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

106

124

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“…We9 and others1011 have identified several clinical factors, including lipid and glucose levels, as well as parameters of iron metabolism, that are associated with the development of steatosis. However, neither clinical characteristics nor laboratory values have yet proved useful for predicting disease development or course121314.…”

mentioning

confidence: 99%

A multi-component classifier for nonalcoholic fatty liver disease (NAFLD) based on genomic, proteomic, and phenomic data domains

Wood¹,

Chu²,

Argyropoulos

et al. 2017

Sci Rep

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Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of conditions that include steatohepatitis and fibrosis that are thought to emanate from hepatic steatosis. Few robust biomarkers or diagnostic tests have been developed for hepatic steatosis in the setting of obesity. We have developed a multi-component classifier for hepatic steatosis comprised of phenotypic, genomic, and proteomic variables using data from 576 adults with extreme obesity who underwent bariatric surgery and intra-operative liver biopsy. Using a 443 patient training set, protein biomarker discovery was performed using the highly multiplexed SOMAscan® proteomic assay, a set of 19 clinical variables, and the steatosis predisposing PNPLA3 rs738409 single nucleotide polymorphism genotype status. The most stable markers were selected using a stability selection algorithm with a L1-regularized logistic regression kernel and were then fitted with logistic regression models to classify steatosis, that were then tested against a 133 sample blinded verification set. The highest area under the ROC curve (AUC) for steatosis of PNPLA3 rs738409 genotype, 8 proteins, or 19 phenotypic variables was 0.913, whereas the final classifier that included variables from all three domains had an AUC of 0.935. These data indicate that multi-domain modeling has better predictive power than comprehensive analysis of variables from a single domain.

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“…A retrospective epidemiological study reveals that the ratio of total cholesterol to HDL-cholesterol is a significant risk factor for advanced NAFLD31. The association of cholesterol with NAFLD has also been reported in other studies33434445.…”

Section: Discussionmentioning

confidence: 58%

“…It has been shown that diets containing excessive amount of fat, especially saturated fatty acids, remarkably increase the risk of obesity and nonalcoholic fatty liver disease (NAFLD)27282930. Additionally, dietary cholesterol has been attributed to the development of NAFLD27313233343536. We have recently reported that FOXOs regulate both total cholesterol and low-density lipoprotein cholesterol725.…”

mentioning

confidence: 99%

FOXO transcription factors protect against the diet-induced fatty liver disease

Pan

Zhang

Kim

et al. 2017

Sci Rep

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Forkhead O transcription factors (FOXOs) have been implicated in glucose and lipid homeostasis; however, the role of FOXOs in the development of nonalcoholic fatty liver disease (NAFLD) is not well understood. In this study, we designed experiments to examine the effects of two different diets—very high fat diet (HFD) and moderately high fat plus cholesterol diet (HFC)—on wildtype (WT) and liver-specific Foxo1/3/4 triple knockout mice (LTKO). Both diets induced severe hepatic steatosis in the LTKO mice as compared to WT controls. However, the HFC diet led to more severe liver injury and fibrosis compared to the HFD diet. At the molecular levels, hepatic Foxo1/3/4 deficiency triggered a significant increase in the expression of inflammatory and fibrotic genes including Emr1, Ccl2, Col1a1, Tgfb, Pdgfrb, and Timp1. Thus, our data suggest that FOXO transcription factors play a salutary role in the protection against the diet-induced fatty liver disease.

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Nonalcoholic fatty liver disease severity is associated with the ratios of total cholesterol and triglycerides to high-density lipoprotein cholesterol

Cited by 91 publications

References 35 publications

Immune cell screening of a nanoparticle library improves atherosclerosis therapy

Immune cell screening of a nanoparticle library improves atherosclerosis therapy

A multi-component classifier for nonalcoholic fatty liver disease (NAFLD) based on genomic, proteomic, and phenomic data domains

FOXO transcription factors protect against the diet-induced fatty liver disease

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