Hepatic expression of the Sptlc3 subunit of serine palmitoyltransferase is associated with the development of hepatocellular carcinoma in a mouse model of nonalcoholic steatohepatitis

Yoshimine, Yozo; Uto, Hirofumi; Kumagai, Kotaro; Mawatari, Seiichi; Arima, Shiho; Ibusuki, Rie; Mera, Kumiko; Nosaki, Tsuyoshi; Kanmura, Shuji; Numata, Masatsugu; Tamai, Tsutomu; Moriuchi, Akihiro; Tsubouchi, Hirohito; Ido, Akio

doi:10.3892/or.2015.3745

Cited by 13 publications

(8 citation statements)

References 34 publications

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“…The expression of the catalytic subunit STPLC3 broadens the substrate specificity of SPT allowing utilization of myristoyl-CoA for synthesis of d16:0 carbon backbone [ 34 ]. However, expression of SPTLC3 subunit is barely detectable in normal liver, although its levels increase in hepatocellular carcinoma [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

Myristic acid potentiates palmitic acid-induced lipotoxicity and steatohepatitis associated with lipodystrophy by sustaning de novo ceramide synthesis

et al. 2015

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Palmitic acid (PA) induces hepatocyte apoptosis and fuels de novo ceramide synthesis in the endoplasmic reticulum (ER). Myristic acid (MA), a free fatty acid highly abundant in copra/palmist oils, is a predictor of nonalcoholic steatohepatitis (NASH) and stimulates ceramide synthesis. Here we investigated the synergism between MA and PA in ceramide synthesis, ER stress, lipotoxicity and NASH. Unlike PA, MA is not lipotoxic but potentiated PA-mediated lipoapoptosis, ER stress, caspase-3 activation and cytochrome c release in primary mouse hepatocytes (PMH). Moreover, MA kinetically sustained PA-induced total ceramide content by stimulating dehydroceramide desaturase and switched the ceramide profile from decreased to increased ceramide 14:0/ceramide16:0, without changing medium and long-chain ceramide species. PMH were more sensitive to equimolar ceramide14:0/ceramide16:0 exposure, which mimics the outcome of PA plus MA treatment on ceramide homeostasis, than to either ceramide alone. Treatment with myriocin to inhibit ceramide synthesis and tauroursodeoxycholic acid to prevent ER stress ameliorated PA plus MA induced apoptosis, similar to the protection afforded by the antioxidant BHA, the pan-caspase inhibitor z-VAD-Fmk and JNK inhibition. Moreover, ruthenium red protected PMH against PA and MA-induced cell death. Recapitulating in vitro findings, mice fed a diet enriched in PA plus MA exhibited lipodystrophy, hepatosplenomegaly, increased liver ceramide content and cholesterol levels, ER stress, liver damage, inflammation and fibrosis compared to mice fed diets enriched in PA or MA alone. The deleterious effects of PA plus MA-enriched diet were largely prevented by in vivo myriocin treatment. These findings indicate a causal link between ceramide synthesis and ER stress in lipotoxicity, and imply that the consumption of diets enriched in MA and PA can cause NASH associated with lipodystrophy.

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Section: Discussionmentioning

confidence: 99%

Myristic acid potentiates palmitic acid-induced lipotoxicity and steatohepatitis associated with lipodystrophy by sustaning de novo ceramide synthesis

et al. 2015

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“…Hematoxylin-eosin (H&E)-stained liver sections were studied under a microscope by blinded observers for evaluation of both, NAFLD Activity Score (NAS; worsening 0–8 scale; 0–3 steatosis; 0–3 inflammation; 0–2 hepatocyte ballooning) and HCC [ 16 – 18 ]. NAS was averaged from three independent observers whereas HCC diagnosis required confirmation from both gross liver and microscopic observation—broad trabecular growth pattern of atypical hepatocytes and clusters of multinucleated hepatocytes—by 2 trained and independent observers [ 17 , 18 ]. At sacrifice, total liver hydroxyproline, a surrogate for collagen, was quantified from liver biopsies using a colorimetric assay as described previously [ 19 ].…”

Section: Methodsmentioning

confidence: 99%

Supervised learning reveals circulating biomarker levels diagnostic of hepatocellular carcinoma in a clinically relevant model of non-alcoholic steatohepatitis; An OAD to NASH

et al. 2018

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Although cirrhosis is a key risk factor for the development of hepatocellular carcinoma (HCC), mounting evidence indicates that in a subset of patients presenting with non-alcoholic steatohepatitis (NASH) HCC manifests in the absence of cirrhosis. Given the sheer size of the ongoing non-alcoholic fatty liver disease (NAFLD) epidemic and the dismal prognosis associated with late-stage primary liver cancer there is an urgent need for HCC surveillance in the NASH population. Using serum levels of HCC biomarkers as vectors and biopsy-proven HCC or no HCC as outputs / binary classifier, a supervised learning campaign was undertaken to develop a minimally invasive technique for making a diagnosis of HCC in a clinically relevant model of NASH. Adult mice randomized to control diet or a fast food diet (FFD) were followed for up to 14 mo and serum level of a panel of HCC-relevant biomarkers was compared with liver biopsies at 3 and 14 mo. Both NAFLD Activity Score (NAS) and hepatic hydroxyproline content were elevated at 3 and 14 mo on FFD. Picrosirius red staining of liver sections revealed a filigree pattern of fibrillar collagen deposition with no cirrhosis at 14 mo on FFD. Nevertheless, 46% of animals bore one or more tumors on their livers confirmed as HCC in hematoxylin-eosin-stained liver sections. In this training set, receiver operating characteristic (ROC) curves analysis for serum levels of the HCC biomarkers osteopontin (OPN), alpha-fetoprotein (AFP) and Dickkopf-1 (DKK1) returned concordance-statistic/area under ROC curve of ≥ 0.89. Serum levels of OPN (threshold, 218 ng/mL; sensitivity, 82%; specificity, 86%), AFP (136 ng/mL; 91%; 97%) and DKK1 (2.4 ng/mL; 82%; 81%) diagnostic for HCC were confirmed in a test set comprising mice on control diet or FFD and mice subjected to hepatic ischemia-reperfusion injury. These data suggest that levels of circulating OPN, AFP and DKK1 can be used to make a diagnosis of HCC in a clinically relevant model of NASH.

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“…Long-term HFD without streptozotocin (STZ) treatment could be an alternative model for non-diabetic NASH with variable onset and characteristics to improve the clinical relevance of the study. Moreover, STAM mice are known as hypertension insensitive and maybe inappropriate to evaluate the anti-hypertensive effects by telmisartan 40 ; however, telmisartan effectively controlled the strong hypertension predictors including plasma TG, LDL and HDL at dose level used in this study. Second, there was no comparison between wild type and STAM mice to evaluate the effect of telmisartan.…”

Section: Discussionmentioning

confidence: 96%

Connectivity mapping of angiotensin-PPAR interactions involved in the amelioration of non-alcoholic steatohepatitis by Telmisartan

Park¹,

Mok

Han

et al. 2019

Sci Rep

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Nonalcoholic fatty liver disease (NAFLD) is a global health problem that is associated with various metabolic disorders. Telmisartan is a potential treatment for NAFLD due to its ability to improve insulin sensitivity and decrease hepatic fat accumulation via modulation of PPARγ, and to suppress hepatic fibrosis by blocking angiotensin II receptors. However, the underlying mechanisms of action of telmisartan have yet to be fully elucidated. In the present study, diabetic nonalcoholic steatohepatitis (NASH) mice (STAM mice) received daily administrations of telmisartan for 6 weeks to assess the improvements in NASH. Hepatic transcriptome analyses revealed that the amelioration of NASH likely occurred through the regulation of inflammatory- and fibrosis-related gene responses. An integrated network analysis including transcriptional and non-transcriptional genes regulated by telmisartan showed that the NAFLD pathway is interconnected with the dysregulated RAS-PPAR-NFκB pathways. The downstream targets of PPARα, PPARδ, and RELA in this network significantly overlapped with telmisartan-induced differentially expressed genes (DEGs), which were verified in palmitate-treated Hepa1c1c7 cell line. This transcriptome approach accompanied with cell-based molecular analyses provided the opportunity to understand the fundamental molecular mechanisms underpinning the therapeutic effects of telmisartan, and will contribute to the establishment of a novel pharmacological treatment for NASH patients.

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Hepatic expression of the Sptlc3 subunit of serine palmitoyltransferase is associated with the development of hepatocellular carcinoma in a mouse model of nonalcoholic steatohepatitis

Cited by 13 publications

References 34 publications

Myristic acid potentiates palmitic acid-induced lipotoxicity and steatohepatitis associated with lipodystrophy by sustaning de novo ceramide synthesis

Myristic acid potentiates palmitic acid-induced lipotoxicity and steatohepatitis associated with lipodystrophy by sustaning de novo ceramide synthesis

Supervised learning reveals circulating biomarker levels diagnostic of hepatocellular carcinoma in a clinically relevant model of non-alcoholic steatohepatitis; An OAD to NASH

Connectivity mapping of angiotensin-PPAR interactions involved in the amelioration of non-alcoholic steatohepatitis by Telmisartan

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