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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

Quantitative real-time PCR (qPCR) analysis of genes involved in steatohepatitis.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 fatty acid and triglyceride synthesis, (B) cholesterol metabolism and (C) carboxylesterase. *P < 0.05, **P < 0.01.
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f6: Quantitative real-time PCR (qPCR) analysis of genes involved in steatohepatitis.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 fatty acid and triglyceride synthesis, (B) cholesterol metabolism and (C) carboxylesterase. *P < 0.05, **P < 0.01.

Mentions: To have some idea on the molecular mechanisms by which an LD results in such a striking phenotype in Elovl6−/−Ldlr−/− mice, mRNA expression of candidate genes in livers from mice of both genotypes fed an SD or an LD diet was examined using quantitative real-time polymerase chain reaction (qPCR). Genes involved in FA synthesis controlled by sterol regulatory element binding protein 1c (Srebf1c), such as fatty acid synthase (Fasn), were significantly increased and stearoyl-CoA desaturase-1 (Scd1) showed a tendency to increase in the livers of LD-fed Elovl6−/−Ldlr−/− mice compared with LD-fed Elovl6+/+Ldlr−/− mice (Fig. 6A). Expression of genes involved in TG synthesis, including glycerol-3-phosphate acyltransferase (Gpam) and diacylglycerol O-acyltransferase 2 (Dgat2), was slightly increased in the livers of LD-fed Elovl6−/−Ldlr−/− mice compared with LD-fed Elovl6+/+Ldlr−/− mice; whereas, expression of diacylglycerol O-acyltransferase 1 (Dgat1) was similar in both genotypes. Expression of genes involved in cholesterol synthesis regulated by sterol regulatory element binding protein 2 (Srebp2), including 3-hydroxy-3-trmethylglutaryl-coenzyme A synthase 1 (Hmgcs1), was decreased, and expression of genes for cholesterol efflux enhanced by liver X receptor α (Lxrα) (nuclear receptor subfamily 1, group H, member 3: Nr1h3), such as ATP-binding cassette sub-family A member 1 (Abca1), ATP-binding cassette sub-family G member 1 (Abcg5), and Abcg8, was increased in response to cholesterol feeding in both groups of mice (Fig. 6B). Expression of acetyl-coenzyme A acetyltransferase 2 (Acat2) was increased in LD-fed Elovl6−/−Ldlr−/− mice compared with LD-fed Elovl6+/+Ldlr−/− mice. The enhanced expression of lipogenic enzymes and Acat2 in the livers of Elovl6−/−Ldlr−/− mice might compensate for the unbalanced FA composition. Expression of carboxylesterase 3a and 3b (Ces3a and Ces3b) was suppressed by the LD in Elovl6+/+Ldlr−/− mice, but was restored by the absence of Elovl6 (Fig. 6C).


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)

Quantitative real-time PCR (qPCR) analysis of genes involved in steatohepatitis.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 fatty acid and triglyceride synthesis, (B) cholesterol metabolism and (C) carboxylesterase. *P < 0.05, **P < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f6: Quantitative real-time PCR (qPCR) analysis of genes involved in steatohepatitis.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 fatty acid and triglyceride synthesis, (B) cholesterol metabolism and (C) carboxylesterase. *P < 0.05, **P < 0.01.
Mentions: To have some idea on the molecular mechanisms by which an LD results in such a striking phenotype in Elovl6−/−Ldlr−/− mice, mRNA expression of candidate genes in livers from mice of both genotypes fed an SD or an LD diet was examined using quantitative real-time polymerase chain reaction (qPCR). Genes involved in FA synthesis controlled by sterol regulatory element binding protein 1c (Srebf1c), such as fatty acid synthase (Fasn), were significantly increased and stearoyl-CoA desaturase-1 (Scd1) showed a tendency to increase in the livers of LD-fed Elovl6−/−Ldlr−/− mice compared with LD-fed Elovl6+/+Ldlr−/− mice (Fig. 6A). Expression of genes involved in TG synthesis, including glycerol-3-phosphate acyltransferase (Gpam) and diacylglycerol O-acyltransferase 2 (Dgat2), was slightly increased in the livers of LD-fed Elovl6−/−Ldlr−/− mice compared with LD-fed Elovl6+/+Ldlr−/− mice; whereas, expression of diacylglycerol O-acyltransferase 1 (Dgat1) was similar in both genotypes. Expression of genes involved in cholesterol synthesis regulated by sterol regulatory element binding protein 2 (Srebp2), including 3-hydroxy-3-trmethylglutaryl-coenzyme A synthase 1 (Hmgcs1), was decreased, and expression of genes for cholesterol efflux enhanced by liver X receptor α (Lxrα) (nuclear receptor subfamily 1, group H, member 3: Nr1h3), such as ATP-binding cassette sub-family A member 1 (Abca1), ATP-binding cassette sub-family G member 1 (Abcg5), and Abcg8, was increased in response to cholesterol feeding in both groups of mice (Fig. 6B). Expression of acetyl-coenzyme A acetyltransferase 2 (Acat2) was increased in LD-fed Elovl6−/−Ldlr−/− mice compared with LD-fed Elovl6+/+Ldlr−/− mice. The enhanced expression of lipogenic enzymes and Acat2 in the livers of Elovl6−/−Ldlr−/− mice might compensate for the unbalanced FA composition. Expression of carboxylesterase 3a and 3b (Ces3a and Ces3b) was suppressed by the LD in Elovl6+/+Ldlr−/− mice, but was restored by the absence of Elovl6 (Fig. 6C).

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