Acyl-CoA:cholesterol acyltransferase 1 mediates liver fibrosis by regulating free cholesterol accumulation in hepatic stellate cells

Tomita, Kengo; Teratani, Toshiaki; Suzuki, Takahiro; Shimizu, Masahiro; Sato, Hírokazu; Narimatsu, Kazuyuki; Usui, Shingo; Furuhashi, Hirotaka; Kimura, Akifumi; Nishiyama, Kiyoshi; Maejima, Tadashi; Okada, Yoshikiyo; Kurihara, Chie; Shimamura, Katsuyoshi; Ebinuma, Hirotoshi; Saito, Hidetsugu; Yokoyama, Hirokazu; Watanabe, Chikako; Komoto, Shunsuke; Nagao, Shigeaki; Sugiyama, Kazuo; Aosasa, Suefumi; Hatsuse, Kazuo; Yamamoto, Junji; Hibi, Toshifumi; Miura, Soichiro; Hokari, Ryota; Kanai, Takanori

doi:10.1016/j.jhep.2014.03.018

Cited by 76 publications

(70 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Obese, diabetic mice accumulate free cholesterol (FC) in the liver [157]. Rodent models have demonstrated the pro-activation effects of FC accumulation within HSCs, through a number of interrelated steps [158][159][160]. FC interferes with the endosomal-lysosomal degradation pathway of TLR4; subsequently, levels of the membrane bound TGFβ pseuodreceptor, BAMBI, are increased, which sensitizes HSCs to profibrogenic stimuli.…”

Section: New and Emerging Pathways Of Hsc Activationmentioning

confidence: 99%

“…FC interferes with the endosomal-lysosomal degradation pathway of TLR4; subsequently, levels of the membrane bound TGFβ pseuodreceptor, BAMBI, are increased, which sensitizes HSCs to profibrogenic stimuli. Furthermore, the disruption of cholesterol homeostasis suppresses PPARγ activity [158][159][160]. The addition of commonly used lipid-lowering drugs may reverse this phenotype [161].…”

Section: New and Emerging Pathways Of Hsc Activationmentioning

confidence: 99%

See 1 more Smart Citation

Stellate Cells and Hepatic Fibrosis

Hasegawa

Wallace

Friedman

2015

Stellate Cells in Health and Disease

View full text Add to dashboard Cite

Section: New and Emerging Pathways Of Hsc Activationmentioning

confidence: 99%

Section: New and Emerging Pathways Of Hsc Activationmentioning

confidence: 99%

Stellate Cells and Hepatic Fibrosis

Hasegawa

Wallace

Friedman

2015

Stellate Cells in Health and Disease

View full text Add to dashboard Cite

“…We noted that genetic deletion of ACAT-2 or treatment with antisense oligonucleotides of ACAT-2 could protect the mouse liver from dietary cholesterol-induced steatosis by facilitating TG secretion to the plasma [36,37]. In the mouse liver, ACAT-2 is primarily expressed in hepatocytes [7]. Although K-604 exhibits 229-fold selectivity in human CHO cell lines [8], it cannot be always reflected in rodent models.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, Tomita, et al [7] proposed that ACAT-1 deficiency leading to FC accumulation could promote liver fibrosis induced by bile duct ligation or carbon tetrachloride. This discrepancy between the previous report and our study may be attributed to the different experimental conditions, such as a complete genetic deficiency of ACAT-1 and its enzyme function.…”

Section: Discussionmentioning

confidence: 99%

“…One of the differences between the K-604 and bezafibrate treatments was the hepatic FC levels (K-604 30 mg/ kg: 6.6, K-604 100 mg/ kg: 7.4 vs. bezafibrate: 10.3 mg/g, Table 2), and the increase in the hepatic FC levels (46% increase) in response to bezafibrate may lead to inflammatory reactions. Of note, Tomita, et al [7] indicated that the FC accumulation in hepatic stellate cells results in enhanced Toll-like receptor 4 signaling and an exacerbation of liver fibrosis [7]. This theory plasma TC levels were increased.…”

Section: Body Weights Plasma Profiles Plasma Concentrations Of K-60mentioning

confidence: 99%

See 1 more Smart Citation

An ACAT-1Inhibitor, K-604, Ameliorates Hepatic Inflammation in NAFLD and NASH Models

Shibata¹,

Shibuya²

2016

JGPLD

View full text Add to dashboard Cite

A high level of cholesterol activates Kupffer cells, which subsequently triggers inflammation and ultimately leads to steatohepatitis. The number of Kupffer cells correlates with the inflammatory grade of Non-Alcoholic Fatty Liver Disease (NAFLD). In this study, we studied the role of 'foamy' Kupffer cells in the nexus between inflammation and steatosis and investigated whether K-604, a selective Acyl-Coenzyme A: Cholesterol Acyltransferase-1 (ACAT-1) inhibitor ameliorates hepatic steatosis and inflammation in rodent models of NAFLD and Non-Alcoholic Steatohepatitis (NASH). Methionine-and Choline-Deficient (MCD) diet-fed KK-Ay mice, High-Fat and High-Cholesterol (HFC) diet-fed Low-Density Lipoprotein Receptor-Deficient (Ldlr(−/−)) mice and Zucker fatty rats were evaluated after 16, 16 and 12 weeks of K-604 treatment. The biochemical parameters, hepatic lipid levels, histopathological changes and gene expression levels were assessed. In the MCD dietfed KK-Ay mice, K-604 significantly improved the NASH symptoms. In the HFC diet-fed Ldlr (−/−) mice, K-604 suppressed the inflammatory gene expression and reduced the number of inflammatory foci. Moreover, K-604 decreased the area and size of foamy Kupffer cells. In the Zucker fatty rats, K-604 could also inhibit hepatic steatosis. These results indicated that K-604 acts directly on Kupffer cells and inhibits hepatic inflammation, suggesting that ACAT-1 is involved in the progression of steatohepatitis. Therefore, ACAT-1 inhibition may be a new therapeutic target for NAFLD and NASH.

show abstract

Chemical Genetic Approaches for the Investigation of Neutral Lipid Metabolism

et al. 2016

View full text Add to dashboard Cite

The coordinated processes of lipid synthesis, degradation, and transport are mediated by enzymes, cofactors, and transport proteins. Accordingly, lipid-metabolizing enzymes represent logical targets for the treatment of dyslipidemia, a major risk factor for type 2 diabetes, atherosclerosis, and other disorders. Small-molecule tool compounds, modulating the functions of such proteins, can substantially facilitate the characterization of target proteins. Such molecules complement genetic studies, and allow time- and dose-dependent control of protein activity in biological systems. This can improve our understanding of physiological processes, give insights into the druggability of target proteins, and might finally result in the development of therapeutic compounds. In this review we summarize the current state of available inhibitors targeting key proteins in neutral lipid metabolism, with a focus on metabolic lipases, acyltransferases, and fatty-acid-binding proteins.

show abstract

Acyl-CoA:cholesterol acyltransferase 1 mediates liver fibrosis by regulating free cholesterol accumulation in hepatic stellate cells

Cited by 76 publications

References 28 publications

Stellate Cells and Hepatic Fibrosis

Stellate Cells and Hepatic Fibrosis

An ACAT-1Inhibitor, K-604, Ameliorates Hepatic Inflammation in NAFLD and NASH Models

Chemical Genetic Approaches for the Investigation of Neutral Lipid Metabolism

Contact Info

Product

Resources

About