Therapeutic reversal of chronic alcohol‐related steatohepatitis with the ceramide inhibitor myriocin

Tong, Ming; Longato, Lisa; Ramírez, Teresa González; Zabala, Valerie; Wands, Jack R.

doi:10.1111/iep.12052

Cited by 36 publications

(28 citation statements)

References 73 publications

(202 reference statements)

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“…For examples, there is a link between the role of glycoceramides and hepatic steatosis in ob/ob mice fed with high-fat diet (29, 30). Ceramide accumulation has also been implicated in alcohol-related steatohepatitis (31, 32). We thus turned our attention to the possible beneficial roles of sphingolipids that contribute to both the nodular steatosis and the expansion of residual gp96+ cells in the liver of KO mice.…”

Section: Resultsmentioning

confidence: 99%

Endoplasmic reticulum heat shock protein gp96 maintains liver homeostasis and promotes hepatocellular carcinogenesis

Rachidi

Sun

et al. 2015

Journal of Hepatology

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Background & Aims gp96, or grp94, is an endoplasmic reticulum (ER) heat shock protein 90 paralog which acts as a protein chaperone and plays an important role in ER homeostasis. Previous work has demonstrated its role in ER stress, Wnt and integrin signaling, calcium homeostasis and others, which are vital processes in oncogenesis. However, the cancer-intrinsic function of gp96 remains controversial. Methods We studied the roles of gp96 in liver biology in mice via an albumin promoter-driven cre recombinase-mediated disruption of gp96 gene, hsp90b1. The impact of gp96 status on hepatic carcinogenesis in response to diethyl-nitrosoamine (DENA) was probed. The roles of gp96 on human hepatocellular carcinoma cells (HCC) were also examined pharmacologically with a targeted gp96 inhibitor. Results We demonstrated that gp96 maintains liver development and hepatocyte function in vivo, and its loss genetically promotes adaptive accumulation of long chain ceramides, accompanied by steatotic regeneration of residual gp96+ hepatocytes. The need for compensatory expansion of gp96+ cells in the gp96− background predisposes mice to develop carcinogen-induced hepatic hyperplasia and cancer from gp96+ but not gp96− hepatocytes. We also found that genetic and pharmacological inhibition of gp96 in human HCCs perturbs multiple growth signals, and attenuates their proliferation and expansion. Conclusions gp96 is a pro-oncogenic chaperone, and is an attractive therapeutic target for HCC.

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Section: Resultsmentioning

confidence: 99%

Endoplasmic reticulum heat shock protein gp96 maintains liver homeostasis and promotes hepatocellular carcinogenesis

Rachidi

Sun

et al. 2015

Journal of Hepatology

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“…A reduction of GSL biosynthesis in the adipose tissue of ob/ob mice restored insulin signaling in isolated ex vivo insulinstimulated adipocytes (168,172,176). The improved adipogenesis was a result of the reduced number of larger adipocytes and increased expression of PPAR␥, insulin-responsive glucose transporter (GLUT)-4, and adipsin (103,107,168,169,172,176). Adiponectin gene expression and protein were increased by AMP-DNM, leading to a decreased inflammation in adipose tissue.…”

Section: Glucosylceramide Synthase Inhibitors and Other Inhibitors Ofmentioning

confidence: 99%

“…Alcohol-related liver disease (ALD) is also associated with altered Cer profiles, steatohepatitis, insulin resistance, disruptions in lipid metabolism in hepatocytes, increased proinflammatory cytokines, dysregulated lipid metabolism, ER, and oxidative stress (53, 169,173). Altered lipid metabolism promotes Cer accumulation and oxidative stress, and these can result in a "lipotoxic state" in which there is activation of ER-stress pathways, inflammation, and insulin resistance (54,143,147).…”

Section: Sl Pathways In Diabetes Nafld and Nashmentioning

confidence: 99%

“…The Cer inhibitor myriocin reduces the severity of ASH by decreasing the abundance and size of lipid droplets and mitochondria and limiting inflammation, thereby improving the architecture of the ER. Myriocin-mediated reductions in hepatic Cer levels enhance insulin signaling through the insulin receptor with a reduced hepatic oxidative stress and modulated ER stress (53, 169,173).…”

Section: Sl Pathways In Diabetes Nafld and Nashmentioning

confidence: 99%

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Compounds of the sphingomyelin-ceramide-glycosphingolipid pathways as secondary messenger molecules: new targets for novel therapies for fatty liver disease and insulin resistance

Ilan

2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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The compounds of sphingomyelin-ceramide-glycosphingolipid pathways have been studied as potential secondary messenger molecules in various systems, along with liver function and insulin resistance. Secondary messenger molecules act directly or indirectly to affect cell organelles and intercellular interactions. Their potential role in the pathogenesis of steatohepatitis and diabetes has been suggested. Data samples collected from patients with Gaucher's disease, who had high levels of glucocerebroside, support a role for compounds from these pathways as a messenger molecules in the pathogenesis of fatty liver disease and diabetes. The present review summarizes some of the recent data on the role of glycosphingolipid molecules as messenger molecules in various physiological and pathological conditions, more specifically including insulin resistance and fatty liver disease.

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“…To minimize the possibility that our observations were the result of nonspecific pharmacological effects, we used inhibitors capable of blocking separate enzymes in the various pathways. First, the fungal toxins myriocin and fumonisin B1 inhibit separate enzymes that are required for de novo ceramide synthesis (19,25), and both protected EPCs from the accumulation of ceramide induced by PA. Second, NOE, an inhibitor of ceramidase (4), was able to aggravated the effect of PAinduced ceramide accumulation. Thus, by using various inhibitors, our data indicated that PA can induce the accumulation of ceramide in EPCs.…”

Section: Discussionmentioning

confidence: 99%

Akt/eNOS signaling pathway mediates inhibition of endothelial progenitor cells by palmitate-induced ceramide

Tan

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Palmitate (PA) impairs endothelial progenitor cells (EPCs). However, the molecular mechanism underlying the suppressive function of PA remains largely unknown. Ceramide, a free fatty acid metabolite, mediates multiple cellular signals. We hypothesized that ceramide acts as an intermediate molecule to mediate inhibition of EPCs by PA. We first demonstrated that PA could inhibit the attachment, migration, and tube formation of EPCs through suppression of the Akt/endothelial nitric oxide (NO) synthase (eNOS) signaling pathway. In addition, we observed that PA could induce ceramide accumulation in EPCs. To test whether the accumulation of ceramide causes EPC dysfunction, the ceramide synthesis inhibitors myriocin and fumonisin B1 were used. We that found both inhibitors could effectively abolish PA-mediated EPC inhibition. Furthermore, the ceramide deacylation inhibitor N-oleoylethanolamine could augment the inhibitory effect of PA on EPCs, indicating that it is ceramide, not its metabolites, that mediates the suppression of EPCs by PA. We have previously shown that Akt/ eNOS phosphorylation was reduced after PA treatment, which, in turn, hampered the normal bioavailability of NO, leading to impaired functions of EPCs. To test the role for ceramide in this process, a clinically used NO donor, sodium nitroprusside, was used. We found that sodium nitroprusside could rescue the suppressive effects of ceramide on EPCs, suggesting that ceramide-mediated EPC inhibition might be through reduction of NO production. Taken together, our findings indicated that ceramide-induced reduction of NO might be the molecular mechanism for PA-mediated EPC inhibition; thus, targeting either ceramide or NO production might be an effective means for improvement of EPC functions in diseases.

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Therapeutic reversal of chronic alcohol‐related steatohepatitis with the ceramide inhibitor myriocin

Cited by 36 publications

References 73 publications

Endoplasmic reticulum heat shock protein gp96 maintains liver homeostasis and promotes hepatocellular carcinogenesis

Endoplasmic reticulum heat shock protein gp96 maintains liver homeostasis and promotes hepatocellular carcinogenesis

Compounds of the sphingomyelin-ceramide-glycosphingolipid pathways as secondary messenger molecules: new targets for novel therapies for fatty liver disease and insulin resistance

Akt/eNOS signaling pathway mediates inhibition of endothelial progenitor cells by palmitate-induced ceramide

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