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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

Plasma lipid and lipoprotein profiles of lithogenic diet (LD)-fed Ldlr−/− mice lacking Elovl6.(A) Plasma total cholesterol (TC), (B) triglyceride (TG), (C) free fatty acid (FFA) and (D) total bile acid (TBA) levels in Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice fed a standard diet (SD) or an LD for 4 weeks (n = 8–13 per group). (E) High performance liquid chromatography lipoprotein profiles of pooled plasma samples from Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice fed an LD for 4 weeks (n = 3–4 per group). Peaks for very low density lipoprotein (VLDL), low density lipoprotein (LDL) and high density lipoprotein (HDL) are indicated. *P < 0.05, **P < 0.01.
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f2: Plasma lipid and lipoprotein profiles of lithogenic diet (LD)-fed Ldlr−/− mice lacking Elovl6.(A) Plasma total cholesterol (TC), (B) triglyceride (TG), (C) free fatty acid (FFA) and (D) total bile acid (TBA) levels in Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice fed a standard diet (SD) or an LD for 4 weeks (n = 8–13 per group). (E) High performance liquid chromatography lipoprotein profiles of pooled plasma samples from Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice fed an LD for 4 weeks (n = 3–4 per group). Peaks for very low density lipoprotein (VLDL), low density lipoprotein (LDL) and high density lipoprotein (HDL) are indicated. *P < 0.05, **P < 0.01.

Mentions: In mice fed an SD, plasma levels of total cholesterol (TC), TG, free fatty acid (FFA) and total bile acid (TBA) were not significantly different between Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice (Fig. 2A–D). After 4 weeks on an LD, plasma TC, TG and TBA levels in Elovl6+/+Ldlr−/− mice were markedly elevated compared with levels in SD-fed Elovl6+/+Ldlr−/− mice as a consequence of dietary loading of cholesterol, fat and cholic acid (CA) in the LD. However, Elovl6−/−Ldlr−/− mice were strongly resistant to these changes caused by the LD. Compared with LD-fed Elovl6+/+Ldlr−/− mice, LD-fed Elovl6−/−Ldlr−/− mice had significantly lower plasma TC, and plasma TBA levels were markedly suppressed (Fig. 2A, D). High-performance liquid chromatography (HPLC) revealed that very low density lipoprotein (VLDL) and LDL cholesterol, the major cholesterol fraction in Ldlr−/− mice on an LD, was reduced and HDL cholesterol was increased in LD-fed Elovl6−/−Ldlr−/− mice compared with LD-fed Elovl6+/+Ldlr−/− mice (Fig. 2E).


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)

Plasma lipid and lipoprotein profiles of lithogenic diet (LD)-fed Ldlr−/− mice lacking Elovl6.(A) Plasma total cholesterol (TC), (B) triglyceride (TG), (C) free fatty acid (FFA) and (D) total bile acid (TBA) levels in Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice fed a standard diet (SD) or an LD for 4 weeks (n = 8–13 per group). (E) High performance liquid chromatography lipoprotein profiles of pooled plasma samples from Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice fed an LD for 4 weeks (n = 3–4 per group). Peaks for very low density lipoprotein (VLDL), low density lipoprotein (LDL) and high density lipoprotein (HDL) are indicated. *P < 0.05, **P < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4664962&req=5

f2: Plasma lipid and lipoprotein profiles of lithogenic diet (LD)-fed Ldlr−/− mice lacking Elovl6.(A) Plasma total cholesterol (TC), (B) triglyceride (TG), (C) free fatty acid (FFA) and (D) total bile acid (TBA) levels in Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice fed a standard diet (SD) or an LD for 4 weeks (n = 8–13 per group). (E) High performance liquid chromatography lipoprotein profiles of pooled plasma samples from Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice fed an LD for 4 weeks (n = 3–4 per group). Peaks for very low density lipoprotein (VLDL), low density lipoprotein (LDL) and high density lipoprotein (HDL) are indicated. *P < 0.05, **P < 0.01.
Mentions: In mice fed an SD, plasma levels of total cholesterol (TC), TG, free fatty acid (FFA) and total bile acid (TBA) were not significantly different between Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice (Fig. 2A–D). After 4 weeks on an LD, plasma TC, TG and TBA levels in Elovl6+/+Ldlr−/− mice were markedly elevated compared with levels in SD-fed Elovl6+/+Ldlr−/− mice as a consequence of dietary loading of cholesterol, fat and cholic acid (CA) in the LD. However, Elovl6−/−Ldlr−/− mice were strongly resistant to these changes caused by the LD. Compared with LD-fed Elovl6+/+Ldlr−/− mice, LD-fed Elovl6−/−Ldlr−/− mice had significantly lower plasma TC, and plasma TBA levels were markedly suppressed (Fig. 2A, D). High-performance liquid chromatography (HPLC) revealed that very low density lipoprotein (VLDL) and LDL cholesterol, the major cholesterol fraction in Ldlr−/− mice on an LD, was reduced and HDL cholesterol was increased in LD-fed Elovl6−/−Ldlr−/− mice compared with LD-fed Elovl6+/+Ldlr−/− mice (Fig. 2E).

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