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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

Hepatic expression levels of genes involved in BA metabolism.Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice were fed a standard diet (SD) or a lithogenic diet (LD) for 4 weeks and sacrificed following 4 h of food deprivation (n = 8–13 per group). (A) qPCR analysis of genes for BA metabolism. *P < 0.05, **P < 0.01. (B) Immunoblot analysis of CYP7A1, CYP27A1, SLC10A1 and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) in the livers of Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice fed a SD or a LD for 4 weeks.
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f7: Hepatic expression levels of genes involved in BA metabolism.Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice were fed a standard diet (SD) or a lithogenic diet (LD) for 4 weeks and sacrificed following 4 h of food deprivation (n = 8–13 per group). (A) qPCR analysis of genes for BA metabolism. *P < 0.05, **P < 0.01. (B) Immunoblot analysis of CYP7A1, CYP27A1, SLC10A1 and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) in the livers of Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice fed a SD or a LD for 4 weeks.

Mentions: The expression of genes associated with BA metabolism was also examined (Fig. 7A). Loss of Elovl6 slightly decreased the expression of farnesoid X receptor (Fxr) (nuclear receptor subfamily 1, group H, member 4: Nr1h4) in mice on the SD but had little effect in the LD-fed mice. The LD increased the expression of the Fxr-target genes, liver receptor homolog-1 (Lrh1) (nuclear receptor subfamily 5, group A, member 2: Nr5a2) and small heterodimer partner (Shp) (nuclear receptor subfamily 0, group B, member 2: Nr0b2), in both genotypes. The biosynthesis of BAs in the liver is controlled by multiple cytochrome P450 (CYP) enzymes28. The LD markedly suppressed mRNA expression of cholesterol 7α-hydroxylase (Cyp7a1) and sterol 12α-hydroxylase (Cyp8b1), the two key enzymes in BA synthesis, in both genotypes. Expression of sterol 27-hydroxylase (Cyp27a1) and oxysterol 7α-hydroxylase (Cyp7b1), which are involved in an alternative pathway of BA synthesis, was also decreased by the LD in Elovl6+/+Ldlr−/− mice, but was significantly upregulated in the livers of LD-fed Elovl6−/−Ldlr−/− mice compared with LD-fed Elovl6+/+Ldlr−/− mice. Expression of solute carrier family 10 member 1 (Slc10a1) and solute carrier organic anion transporter family member 1a1 (Slco1a1), which are involved in BA uptake by hepatocytes, was suppressed by the LD in Elovl6+/+Ldlr−/− mice. Strikingly, LD-fed Elovl6−/−Ldlr−/− mice displayed a complete lack of Slc10a1 and Slco1a1 suppression. Expression of ATP-binding cassette sub-family B member 11 (Abcb11), an ABC transporter responsible for the transport of bile salt from hepatocytes into the bile, was significantly upregulated in the livers by the LD with greater intensity in Elovl6−/−Ldlr−/− mice compared to LD Elovl6+/+Ldlr−/− mice. Expression of ATP-binding cassette subfamily C member 1 (Abcc1), Abcc3 and Abcc4, which are involved in basolateral BA excretion, was markedly elevated in LD-fed Elovl6+/+Ldlr−/− mice. The expression of Abcc1 was significantly decreased, and Abcc4 tended to decrease (P = 0.059) in LD-fed Elovl6−/−Ldlr−/− mice compared with LD-fed Elovl6+/+Ldlr−/− mice. Consistently with mRNA levels, hepatic CYP7A1 protein was suppressed by LD feeding in both genotypes (Fig. 7B). Hepatic protein levels of CYP27a1 and SLC10A1 was also decreased by the LD in Elovl6+/+Ldlr−/− mice, but was upregulated in LD-fed Elovl6−/−Ldlr−/− mice compared with LD-fed Elovl6+/+Ldlr−/− mice.


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)

Hepatic expression levels of genes involved in BA metabolism.Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice were fed a standard diet (SD) or a lithogenic diet (LD) for 4 weeks and sacrificed following 4 h of food deprivation (n = 8–13 per group). (A) qPCR analysis of genes for BA metabolism. *P < 0.05, **P < 0.01. (B) Immunoblot analysis of CYP7A1, CYP27A1, SLC10A1 and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) in the livers of Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice fed a SD or a LD for 4 weeks.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4664962&req=5

f7: Hepatic expression levels of genes involved in BA metabolism.Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice were fed a standard diet (SD) or a lithogenic diet (LD) for 4 weeks and sacrificed following 4 h of food deprivation (n = 8–13 per group). (A) qPCR analysis of genes for BA metabolism. *P < 0.05, **P < 0.01. (B) Immunoblot analysis of CYP7A1, CYP27A1, SLC10A1 and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) in the livers of Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice fed a SD or a LD for 4 weeks.
Mentions: The expression of genes associated with BA metabolism was also examined (Fig. 7A). Loss of Elovl6 slightly decreased the expression of farnesoid X receptor (Fxr) (nuclear receptor subfamily 1, group H, member 4: Nr1h4) in mice on the SD but had little effect in the LD-fed mice. The LD increased the expression of the Fxr-target genes, liver receptor homolog-1 (Lrh1) (nuclear receptor subfamily 5, group A, member 2: Nr5a2) and small heterodimer partner (Shp) (nuclear receptor subfamily 0, group B, member 2: Nr0b2), in both genotypes. The biosynthesis of BAs in the liver is controlled by multiple cytochrome P450 (CYP) enzymes28. The LD markedly suppressed mRNA expression of cholesterol 7α-hydroxylase (Cyp7a1) and sterol 12α-hydroxylase (Cyp8b1), the two key enzymes in BA synthesis, in both genotypes. Expression of sterol 27-hydroxylase (Cyp27a1) and oxysterol 7α-hydroxylase (Cyp7b1), which are involved in an alternative pathway of BA synthesis, was also decreased by the LD in Elovl6+/+Ldlr−/− mice, but was significantly upregulated in the livers of LD-fed Elovl6−/−Ldlr−/− mice compared with LD-fed Elovl6+/+Ldlr−/− mice. Expression of solute carrier family 10 member 1 (Slc10a1) and solute carrier organic anion transporter family member 1a1 (Slco1a1), which are involved in BA uptake by hepatocytes, was suppressed by the LD in Elovl6+/+Ldlr−/− mice. Strikingly, LD-fed Elovl6−/−Ldlr−/− mice displayed a complete lack of Slc10a1 and Slco1a1 suppression. Expression of ATP-binding cassette sub-family B member 11 (Abcb11), an ABC transporter responsible for the transport of bile salt from hepatocytes into the bile, was significantly upregulated in the livers by the LD with greater intensity in Elovl6−/−Ldlr−/− mice compared to LD Elovl6+/+Ldlr−/− mice. Expression of ATP-binding cassette subfamily C member 1 (Abcc1), Abcc3 and Abcc4, which are involved in basolateral BA excretion, was markedly elevated in LD-fed Elovl6+/+Ldlr−/− mice. The expression of Abcc1 was significantly decreased, and Abcc4 tended to decrease (P = 0.059) in LD-fed Elovl6−/−Ldlr−/− mice compared with LD-fed Elovl6+/+Ldlr−/− mice. Consistently with mRNA levels, hepatic CYP7A1 protein was suppressed by LD feeding in both genotypes (Fig. 7B). Hepatic protein levels of CYP27a1 and SLC10A1 was also decreased by the LD in Elovl6+/+Ldlr−/− mice, but was upregulated in LD-fed Elovl6−/−Ldlr−/− mice compared with LD-fed Elovl6+/+Ldlr−/− mice.

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