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Absence of Elovl6 attenuates steatohepatitis but promotes gallstone formation in a lithogenic diet-fed Ldlr(-/-) mouse model.

Kuba M, Matsuzaka T, Matsumori R, Saito R, Kaga N, Taka H, Ikehata K, Okada N, Kikuchi T, Ohno H, Han SI, Takeuchi Y, Kobayashi K, Iwasaki H, Yatoh S, Suzuki H, Sone H, Yahagi N, Arakawa Y, Fujimura T, Nakagawa Y, Yamada N, Shimano H - Sci Rep (2015)

Bottom Line: We have previously shown that Elovl6 plays an important role in the development of hepatic insulin resistance and NASH by modifying FA composition.Recent studies have linked altered hepatic cholesterol homeostasis and cholesterol accumulation to the pathogenesis of NASH.The absence of Elovl6 also decreases hepatic inflammation, oxidative stress and liver injury, but increases the formation of cholesterol crystals in the less dilated gallbladder.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.

ABSTRACT
Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease (NAFLD) that can develop into liver cirrhosis and cancer. Elongation of very long chain fatty acids (ELOVL) family member 6 (Elovl6) is a microsomal enzyme that regulates the elongation of C12-16 saturated and monounsaturated fatty acids (FAs). We have previously shown that Elovl6 plays an important role in the development of hepatic insulin resistance and NASH by modifying FA composition. Recent studies have linked altered hepatic cholesterol homeostasis and cholesterol accumulation to the pathogenesis of NASH. In the present study, we further investigated the role of Elovl6 in the progression of lithogenic diet (LD)-induced steatohepatitis. We showed that the absence of Elovl6 suppresses hepatic lipid accumulation, plasma total cholesterol and total bile acid (BA) levels in LDL receptor-deficient (Ldlr(-/-)) mice challenged with a LD. The absence of Elovl6 also decreases hepatic inflammation, oxidative stress and liver injury, but increases the formation of cholesterol crystals in the less dilated gallbladder. These findings suggest that Elovl6-mediated changes in hepatic FA composition, especially oleic acid (C18:1n-9), control handling of hepatic cholesterol and BA, which protects against hepatotoxicity and steatohepatitis, but promotes gallstone formation in LD-fed Ldlr(-/-) mice.

No MeSH data available.


Related in: MedlinePlus

Effects of Elovl6 deficiency on hepatic mRNA and levels of proteins involved in inflammation, oxidative stress and fibrosis.(A–C) Quantitative real-time PCR (qPCR) analysis of genes for inflammation (A), reactive oxygen species (ROS) generation (B) and fibrogenesis (C). (D) Immunoblot analysis of phosphorylated and total anti-phospho-c-Jun N-terminal kinase (JNK), α-smooth muscle actin (α-SMA) and GAPDH in the livers of Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice fed a standard diet (SD) or a lithogenic diet (LD) for 4 weeks. (E) Ratio between phosphorylated and total JNK and α-SMA and GAPDH on densitometry analysis (n = 2–4 per group). *P < 0.05, **P < 0.01.
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f8: Effects of Elovl6 deficiency on hepatic mRNA and levels of proteins involved in inflammation, oxidative stress and fibrosis.(A–C) Quantitative real-time PCR (qPCR) analysis of genes for inflammation (A), reactive oxygen species (ROS) generation (B) and fibrogenesis (C). (D) Immunoblot analysis of phosphorylated and total anti-phospho-c-Jun N-terminal kinase (JNK), α-smooth muscle actin (α-SMA) and GAPDH in the livers of Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice fed a standard diet (SD) or a lithogenic diet (LD) for 4 weeks. (E) Ratio between phosphorylated and total JNK and α-SMA and GAPDH on densitometry analysis (n = 2–4 per group). *P < 0.05, **P < 0.01.

Mentions: Hepatic damage in LD-fed Ldlr−/− mice is associated with hepatic inflammation, oxidative stress and fibrosis. In agreement with histological and metabolic observations (Fig. 4), inflammatory response genes including tumour necrosis factor α (Tnfα), interleukin 1 β (Il-1b), toll-like receptor 4 (Tlr4), CD14 antigen (Cd14) and secreted phosphoprotein 1 (Spp1) were upregulated in the livers of LD-fed Elovl6+/+Ldlr−/− mice (Fig. 8A). However, induction of these genes showed marked or a trend to suppression in LD-fed Elovl6−/−Ldlr−/− mice. The expression levels of genes for the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex, neutrophil cytosolic factor 1 (Ncf1), neutrophil cytosolic factor 2 (Ncf2) and cytochrome b-245 beta polypeptide (Cybb), were upregulated in LD-fed Elovl6+/+Ldlr−/− mice, but significantly decreased in LD-fed Elovl6−/−Ldlr−/− mice compared with LD-fed Elovl6+/+Ldlr−/− mice (Fig. 8B). The expression level of the gene for transforming growth factor β 1 (Tgfb1) was upregulated in LD-fed Elovl6+/+Ldlr−/− mice but suppressed in LD-fed Elovl6−/−Ldlr−/− mice compared with LD-fed Elovl6+/+Ldlr−/− mice (Fig. 8C). Decreased hepatic inflammation, oxidative stress and fibrosis in Elovl6−/−Ldlr−/− mice were further examined by measuring stresses and proinflammatory pathways. Elovl6 deficiency significantly attenuated LD-induced c-Jun N-terminal kinase (JNK) activation and α-smooth muscle actin (α-SMA) levels in Ldlr−/− mice (Fig. 8D,E).


Absence of Elovl6 attenuates steatohepatitis but promotes gallstone formation in a lithogenic diet-fed Ldlr(-/-) mouse model.

Kuba M, Matsuzaka T, Matsumori R, Saito R, Kaga N, Taka H, Ikehata K, Okada N, Kikuchi T, Ohno H, Han SI, Takeuchi Y, Kobayashi K, Iwasaki H, Yatoh S, Suzuki H, Sone H, Yahagi N, Arakawa Y, Fujimura T, Nakagawa Y, Yamada N, Shimano H - Sci Rep (2015)

Effects of Elovl6 deficiency on hepatic mRNA and levels of proteins involved in inflammation, oxidative stress and fibrosis.(A–C) Quantitative real-time PCR (qPCR) analysis of genes for inflammation (A), reactive oxygen species (ROS) generation (B) and fibrogenesis (C). (D) Immunoblot analysis of phosphorylated and total anti-phospho-c-Jun N-terminal kinase (JNK), α-smooth muscle actin (α-SMA) and GAPDH in the livers of Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice fed a standard diet (SD) or a lithogenic diet (LD) for 4 weeks. (E) Ratio between phosphorylated and total JNK and α-SMA and GAPDH on densitometry analysis (n = 2–4 per group). *P < 0.05, **P < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4664962&req=5

f8: Effects of Elovl6 deficiency on hepatic mRNA and levels of proteins involved in inflammation, oxidative stress and fibrosis.(A–C) Quantitative real-time PCR (qPCR) analysis of genes for inflammation (A), reactive oxygen species (ROS) generation (B) and fibrogenesis (C). (D) Immunoblot analysis of phosphorylated and total anti-phospho-c-Jun N-terminal kinase (JNK), α-smooth muscle actin (α-SMA) and GAPDH in the livers of Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice fed a standard diet (SD) or a lithogenic diet (LD) for 4 weeks. (E) Ratio between phosphorylated and total JNK and α-SMA and GAPDH on densitometry analysis (n = 2–4 per group). *P < 0.05, **P < 0.01.
Mentions: Hepatic damage in LD-fed Ldlr−/− mice is associated with hepatic inflammation, oxidative stress and fibrosis. In agreement with histological and metabolic observations (Fig. 4), inflammatory response genes including tumour necrosis factor α (Tnfα), interleukin 1 β (Il-1b), toll-like receptor 4 (Tlr4), CD14 antigen (Cd14) and secreted phosphoprotein 1 (Spp1) were upregulated in the livers of LD-fed Elovl6+/+Ldlr−/− mice (Fig. 8A). However, induction of these genes showed marked or a trend to suppression in LD-fed Elovl6−/−Ldlr−/− mice. The expression levels of genes for the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex, neutrophil cytosolic factor 1 (Ncf1), neutrophil cytosolic factor 2 (Ncf2) and cytochrome b-245 beta polypeptide (Cybb), were upregulated in LD-fed Elovl6+/+Ldlr−/− mice, but significantly decreased in LD-fed Elovl6−/−Ldlr−/− mice compared with LD-fed Elovl6+/+Ldlr−/− mice (Fig. 8B). The expression level of the gene for transforming growth factor β 1 (Tgfb1) was upregulated in LD-fed Elovl6+/+Ldlr−/− mice but suppressed in LD-fed Elovl6−/−Ldlr−/− mice compared with LD-fed Elovl6+/+Ldlr−/− mice (Fig. 8C). Decreased hepatic inflammation, oxidative stress and fibrosis in Elovl6−/−Ldlr−/− mice were further examined by measuring stresses and proinflammatory pathways. Elovl6 deficiency significantly attenuated LD-induced c-Jun N-terminal kinase (JNK) activation and α-smooth muscle actin (α-SMA) levels in Ldlr−/− mice (Fig. 8D,E).

Bottom Line: We have previously shown that Elovl6 plays an important role in the development of hepatic insulin resistance and NASH by modifying FA composition.Recent studies have linked altered hepatic cholesterol homeostasis and cholesterol accumulation to the pathogenesis of NASH.The absence of Elovl6 also decreases hepatic inflammation, oxidative stress and liver injury, but increases the formation of cholesterol crystals in the less dilated gallbladder.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.

ABSTRACT
Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease (NAFLD) that can develop into liver cirrhosis and cancer. Elongation of very long chain fatty acids (ELOVL) family member 6 (Elovl6) is a microsomal enzyme that regulates the elongation of C12-16 saturated and monounsaturated fatty acids (FAs). We have previously shown that Elovl6 plays an important role in the development of hepatic insulin resistance and NASH by modifying FA composition. Recent studies have linked altered hepatic cholesterol homeostasis and cholesterol accumulation to the pathogenesis of NASH. In the present study, we further investigated the role of Elovl6 in the progression of lithogenic diet (LD)-induced steatohepatitis. We showed that the absence of Elovl6 suppresses hepatic lipid accumulation, plasma total cholesterol and total bile acid (BA) levels in LDL receptor-deficient (Ldlr(-/-)) mice challenged with a LD. The absence of Elovl6 also decreases hepatic inflammation, oxidative stress and liver injury, but increases the formation of cholesterol crystals in the less dilated gallbladder. These findings suggest that Elovl6-mediated changes in hepatic FA composition, especially oleic acid (C18:1n-9), control handling of hepatic cholesterol and BA, which protects against hepatotoxicity and steatohepatitis, but promotes gallstone formation in LD-fed Ldlr(-/-) mice.

No MeSH data available.


Related in: MedlinePlus