Limits...
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 fatty acid composition.(A) Hepatic fatty acid composition for total lipids, (B) the cholesterol ester (CE) fraction, (C) the triglyceride (TG) fraction and (D) the phospholipid (PL) fraction in livers from Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice fed a standard diet (SD) or a lithogenic diet (LD) for 4 weeks. Hepatic total lipids were extracted, and the major classes of lipids were separated on a silica column. The lipid fractions were methyl-esterified and quantified by gas chromatography (n = 3–6 per group). *P < 0.05, **P < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4664962&req=5

f5: Hepatic fatty acid composition.(A) Hepatic fatty acid composition for total lipids, (B) the cholesterol ester (CE) fraction, (C) the triglyceride (TG) fraction and (D) the phospholipid (PL) fraction in livers from Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice fed a standard diet (SD) or a lithogenic diet (LD) for 4 weeks. Hepatic total lipids were extracted, and the major classes of lipids were separated on a silica column. The lipid fractions were methyl-esterified and quantified by gas chromatography (n = 3–6 per group). *P < 0.05, **P < 0.01.

Mentions: FA composition analysis identified that lack of Elovl6 modified the FA profiles of total lipid, cholesterol ester (CE), TG and PL fractions in the livers of Ldlr−/− mice fed an SD or an LD (Fig. 5). Compared with SD-fed Elovl6+/+Ldlr−/− mice, the total lipid fractions of SD-fed Elovl6−/−Ldlr−/− mice had increased C16:0 and C18:2n-6 and decreased C20:3n-6, C22:0 and C24:0 (Fig. 5A). Compared with LD-fed Elovl6+/+Ldlr−/− mice, the total lipid fractions of LD-fed Elovl6−/−Ldlr−/− mice had increased C16:0 and a tendency toward decreased C18:1n-9. In the CE fraction, compared with LD-fed Elovl6+/+Ldlr−/− mice, the livers of the LD-fed Elovl6−/−Ldlr−/− mice had a decreased relative amount of C18:1n-9, whereas the relative amount of C16:0 was increased (Fig. 5B). In the TG fraction, the only significant difference between the groups was increased C16:0 in the livers of SD-fed Elovl6−/−Ldlr−/− mice compared with SD-fed Elovl6+/+Ldlr−/− mice (Fig. 5C). In the PL fraction, the relative amounts of C16:0 and C16:1n-7 were increased in the livers of SD-fed Elovl6−/−Ldlr−/− mice compared with SD-fed Elovl6+/+Ldlr−/− mice (Fig. 5D). In the PL fraction in LD-fed mice, the relative amounts of C12:0, C14:0, C16:0, C16:1n-7, and C18:0 were increased and the relative amounts of C18:1n-9 and C24:1n-9 were decreased in the livers of Elovl6−/−Ldlr−/− mice compared with Elovl6+/+Ldlr−/− mice. Despite different degrees of change depending on the lipid fraction, the overall changes in FA composition in both genotypes were consistent with Elovl6 enzymatic activity.


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 fatty acid composition.(A) Hepatic fatty acid composition for total lipids, (B) the cholesterol ester (CE) fraction, (C) the triglyceride (TG) fraction and (D) the phospholipid (PL) fraction in livers from Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice fed a standard diet (SD) or a lithogenic diet (LD) for 4 weeks. Hepatic total lipids were extracted, and the major classes of lipids were separated on a silica column. The lipid fractions were methyl-esterified and quantified by gas chromatography (n = 3–6 per group). *P < 0.05, **P < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f5: Hepatic fatty acid composition.(A) Hepatic fatty acid composition for total lipids, (B) the cholesterol ester (CE) fraction, (C) the triglyceride (TG) fraction and (D) the phospholipid (PL) fraction in livers from Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice fed a standard diet (SD) or a lithogenic diet (LD) for 4 weeks. Hepatic total lipids were extracted, and the major classes of lipids were separated on a silica column. The lipid fractions were methyl-esterified and quantified by gas chromatography (n = 3–6 per group). *P < 0.05, **P < 0.01.
Mentions: FA composition analysis identified that lack of Elovl6 modified the FA profiles of total lipid, cholesterol ester (CE), TG and PL fractions in the livers of Ldlr−/− mice fed an SD or an LD (Fig. 5). Compared with SD-fed Elovl6+/+Ldlr−/− mice, the total lipid fractions of SD-fed Elovl6−/−Ldlr−/− mice had increased C16:0 and C18:2n-6 and decreased C20:3n-6, C22:0 and C24:0 (Fig. 5A). Compared with LD-fed Elovl6+/+Ldlr−/− mice, the total lipid fractions of LD-fed Elovl6−/−Ldlr−/− mice had increased C16:0 and a tendency toward decreased C18:1n-9. In the CE fraction, compared with LD-fed Elovl6+/+Ldlr−/− mice, the livers of the LD-fed Elovl6−/−Ldlr−/− mice had a decreased relative amount of C18:1n-9, whereas the relative amount of C16:0 was increased (Fig. 5B). In the TG fraction, the only significant difference between the groups was increased C16:0 in the livers of SD-fed Elovl6−/−Ldlr−/− mice compared with SD-fed Elovl6+/+Ldlr−/− mice (Fig. 5C). In the PL fraction, the relative amounts of C16:0 and C16:1n-7 were increased in the livers of SD-fed Elovl6−/−Ldlr−/− mice compared with SD-fed Elovl6+/+Ldlr−/− mice (Fig. 5D). In the PL fraction in LD-fed mice, the relative amounts of C12:0, C14:0, C16:0, C16:1n-7, and C18:0 were increased and the relative amounts of C18:1n-9 and C24:1n-9 were decreased in the livers of Elovl6−/−Ldlr−/− mice compared with Elovl6+/+Ldlr−/− mice. Despite different degrees of change depending on the lipid fraction, the overall changes in FA composition in both genotypes were consistent with Elovl6 enzymatic activity.

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