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The Effects of Endoplasmic-Reticulum-Resident Selenoproteins in a Nonalcoholic Fatty Liver Disease Pig Model Induced by a High-Fat Diet.

ABSTRACT: The present study aimed to investigate the intervention of selenium in the oxidative stress and apoptosis of pig livers, which were induced by a high-fat diet, and the effects of four endoplasmic reticulum (ER)-resident selenoproteins in the process. A 2×4 design trial was conducted that included two dietary fat levels (BD = basal diet and HFD = high-fat diet) and four dietary Se supplementation levels (0, 0.3, 1.0, and 3.0 mg/kg of the diet, in the form of sodium selenite (Na2SeO3)). Our results indicated that the HFD significantly increased the activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the serum, as well as the degree of steatosis, the content of malondialdehyde (MDA), the apoptotic rate, and the level of mRNA caspase-3 in the liver compared to their BD counterparts (p < 0.05). Moreover, these parameters in the HFD groups were more significantly reduced (p < 0.05) for a Se concentration of 1.0 mg/kg than for the other concentrations. Further, for both the BD and HFD, the groups supplemented with 1.0 mg/kg Se showed the highest mRNA level of selenoprotein S. In conclusion, the consumption of an HFD can induce oxidative damage and apoptosis in the liver. This shows that the supplementation of Se at 1.0 mg/kg may be the optimum concentration against damage induced by HFD, and Sels may play a key role in this process.

SUBMITTER: Wang P

PROVIDER: S-EPMC7146353 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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The Effects of Endoplasmic-Reticulum-Resident Selenoproteins in a Nonalcoholic Fatty Liver Disease Pig Model Induced by a High-Fat Diet.

Wang Pengzu P Lu Zhuang Z He Meng M Shi Baoming B Lei Xingen X Shan Anshan A

Nutrients 20200304 3

The present study aimed to investigate the intervention of selenium in the oxidative stress and apoptosis of pig livers, which were induced by a high-fat diet, and the effects of four endoplasmic reticulum (ER)-resident selenoproteins in the process. A 2×4 design trial was conducted that included two dietary fat levels (BD = basal diet and HFD = high-fat diet) and four dietary Se supplementation levels (0, 0.3, 1.0, and 3.0 mg/kg of the diet, in the form of sodium selenite (Na<sub>2</sub>SeO<sub ...[more]

PMID: 32143527

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Project description:BACKGROUND & AIMS:Disruption to endoplasmic reticulum (ER) calcium homeostasis has been implicated in obesity, however, the ability to longitudinally monitor ER calcium fluctuations has been challenging with prior methodologies. We recently described the development of a Gaussia luciferase (GLuc)-based reporter protein responsive to ER calcium depletion (GLuc-SERCaMP) and investigated the effect of a high fat diet on ER calcium homeostasis. METHODS:A GLuc-based reporter cell line was treated with palmitate, a free fatty acid. Rats intrahepatically injected with GLuc-SERCaMP reporter were fed a cafeteria diet or high fat diet. The liver and plasma were examined for established markers of steatosis and compared to plasma levels of SERCaMP activity. RESULTS:Palmitate induced GLuc-SERCaMP release in vitro, indicating ER calcium depletion. Consumption of a cafeteria diet or high fat pellets correlated with alterations to hepatic ER calcium homeostasis in rats, shown by increased GLuc-SERCaMP release. Access to ad lib high fat pellets also led to a corresponding decrease in microsomal calcium ATPase activity and an increase in markers of hepatic steatosis. In addition to GLuc-SERCaMP, we have also identified endogenous proteins (endogenous SERCaMPs) with a similar response to ER calcium depletion. We demonstrated the release of an endogenous SERCaMP, thought to be a liver esterase, during access to a high fat diet. Attenuation of both GLuc-SERCaMP and endogenous SERCaMP was observed during dantrolene administration. CONCLUSIONS:Here we describe the use of a reporter for in vitro and in vivo models of high fat diet. Our results support the theory that dietary fat intake correlates with a decrease in ER calcium levels in the liver and suggest a high fat diet alters the ER proteome. Lay summary: ER calcium dysregulation was observed in rats fed a cafeteria diet or high fat pellets, with fluctuations in sensor release correlating with fat intake. Attenuation of sensor release, as well as food intake was observed during administration of dantrolene, a drug that stabilizes ER calcium. The study describes a novel technique for liver research and provides insight into cellular processes that may contribute to the pathogenesis of obesity and fatty liver disease.

Project description:The pathological progression of nonalcoholic fatty liver disease (NAFLD) is driven by multiple factors, and nonalcoholic steatohepatitis (NASH) represents its progressive form. In our previous studies, we found that bicyclol had beneficial effects on NAFLD/NASH. Here we aim to investigate the underlying molecular mechanisms of the bicyclol effect on NAFLD/NASH induced by high-fat diet (HFD) feeding. A mice model of NAFLD/NASH induced by HFD-feeding for 8 weeks was used. As a pretreatment, bicyclol (200 mg/kg) was given to mice by oral gavage twice daily. Hematoxylin and eosin (H&E) stains were processed to evaluate hepatic steatosis, and hepatic fibrous hyperplasia was assessed by Masson staining. Biochemistry analyses were used to measure serum aminotransferase, serum lipids, and lipids in liver tissues. Proteomics and bioinformatics analyses were performed to identify the signaling pathways and target proteins. The real-time RT-PCR and Western blot analyses were performed to verify the proteomics data. As a result, bicyclol had a markedly protective effect against NAFLD/NASH by suppressing the increase of serum aminotransferase, hepatic lipid accumulation and alleviating histopathological changes in liver tissues. Proteomics analyses showed that bicyclol remarkably restored major pathways related to immunological responses and metabolic processes altered by HFD feeding. Consistent with our previous results, bicyclol significantly inhibited inflammation and oxidative stress pathway related indexes (SAA1, GSTM1 and RDH11). Furthermore, the beneficial effects of bicyclol were closely associated with the signaling pathways of bile acid metabolism (NPC1, SLCOLA4 and UGT1A1), cytochrome P450-mediated metabolism (CYP2C54, CYP2C70 and CYP3A25), biological processes such as metal ion metabolism (Ceruloplasmin and Metallothionein-1), angiogenesis (ALDH1A1) and immunological responses (IFI204 and IFIT3). These findings suggested that bicyclol is a potential preventive agent for NAFLD/NASH by targeting multiple mechanisms in future clinical investigations.

Dataset Information

The Effects of Endoplasmic-Reticulum-Resident Selenoproteins in a Nonalcoholic Fatty Liver Disease Pig Model Induced by a High-Fat Diet.

Publications

The Effects of Endoplasmic-Reticulum-Resident Selenoproteins in a Nonalcoholic Fatty Liver Disease Pig Model Induced by a High-Fat Diet.

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