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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

Total body, liver, white adipose tissue (WAT) and gallbladder weights of Ldlr−/− mice lacking Elovl6.(A) Whole body, (B) liver, (C) gallbladder and (D) perigonadal WAT weights were measured in Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice fed a standard diet (SD) or a lithogenic diet (LD) for 4 weeks (n = 8–13 per group, *P < 0.05, **P < 0.01).
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f1: Total body, liver, white adipose tissue (WAT) and gallbladder weights of Ldlr−/− mice lacking Elovl6.(A) Whole body, (B) liver, (C) gallbladder and (D) perigonadal WAT weights were measured in Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice fed a standard diet (SD) or a lithogenic diet (LD) for 4 weeks (n = 8–13 per group, *P < 0.05, **P < 0.01).

Mentions: Elovl6 and LDLR deficient mice were crossed to generate mice with deficiencies of both Elovl6 (Elovl6−/−) and LDLR (Ldlr−/−). Mice aged 11–16 weeks were fed a standard diet (SD) or an LD for 4 weeks. On an SD, Elovl6−/−Ldlr−/− mice had similar body weight to the Elovl6+/+Ldlr−/− mice (Fig. 1A). The LD showed a trend to decrease body weight in Elovl6+/+Ldlr−/− mice and to increase body weight in Elovl6−/−Ldlr−/− mice. As a result, LD-fed Elovl6+/+Ldlr−/− mice were significantly lighter than LD-fed Elovl6−/−Ldlr−/− mice. Daily food intake in LD-fed Elovl6−/−Ldlr−/− mice was not significantly different compared with LD-fed Elovl6+/+Ldlr−/− mice. The LD for 4 weeks increased liver weights in both Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice compared with their SD-fed counterparts, but Elovl6−/−Ldlr−/− mice showed less LD-induced liver weight gain compared with Elovl6+/+Ldlr−/− mice (Fig. 1B). It is well known that an LD increases the amount of bile, leads to supersaturation of the bile with cholesterol and increases susceptibility to gallstone formation. Supporting this, gallbladder weights were markedly increased in LD-fed Elovl6+/+Ldlr−/− mice (Fig. 1C). Conversely, absence of Elovl6 abolished LD-induced gallbladder enlargement, indicating a decrease in the amount of bile in Elovl6−/−Ldlr−/− mice. LD-fed Elovl6+/+Ldlr−/− mice exhibited significant reductions in epididymal white adipose tissue (WAT) weight compared with SD-fed Elovl6+/+Ldlr−/− mice (Fig. 1D). In contrast, there was no significant difference in WAT weight between LD-fed and SD-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)

Total body, liver, white adipose tissue (WAT) and gallbladder weights of Ldlr−/− mice lacking Elovl6.(A) Whole body, (B) liver, (C) gallbladder and (D) perigonadal WAT weights were measured in Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice fed a standard diet (SD) or a lithogenic diet (LD) for 4 weeks (n = 8–13 per group, *P < 0.05, **P < 0.01).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: Total body, liver, white adipose tissue (WAT) and gallbladder weights of Ldlr−/− mice lacking Elovl6.(A) Whole body, (B) liver, (C) gallbladder and (D) perigonadal WAT weights were measured in Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice fed a standard diet (SD) or a lithogenic diet (LD) for 4 weeks (n = 8–13 per group, *P < 0.05, **P < 0.01).
Mentions: Elovl6 and LDLR deficient mice were crossed to generate mice with deficiencies of both Elovl6 (Elovl6−/−) and LDLR (Ldlr−/−). Mice aged 11–16 weeks were fed a standard diet (SD) or an LD for 4 weeks. On an SD, Elovl6−/−Ldlr−/− mice had similar body weight to the Elovl6+/+Ldlr−/− mice (Fig. 1A). The LD showed a trend to decrease body weight in Elovl6+/+Ldlr−/− mice and to increase body weight in Elovl6−/−Ldlr−/− mice. As a result, LD-fed Elovl6+/+Ldlr−/− mice were significantly lighter than LD-fed Elovl6−/−Ldlr−/− mice. Daily food intake in LD-fed Elovl6−/−Ldlr−/− mice was not significantly different compared with LD-fed Elovl6+/+Ldlr−/− mice. The LD for 4 weeks increased liver weights in both Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice compared with their SD-fed counterparts, but Elovl6−/−Ldlr−/− mice showed less LD-induced liver weight gain compared with Elovl6+/+Ldlr−/− mice (Fig. 1B). It is well known that an LD increases the amount of bile, leads to supersaturation of the bile with cholesterol and increases susceptibility to gallstone formation. Supporting this, gallbladder weights were markedly increased in LD-fed Elovl6+/+Ldlr−/− mice (Fig. 1C). Conversely, absence of Elovl6 abolished LD-induced gallbladder enlargement, indicating a decrease in the amount of bile in Elovl6−/−Ldlr−/− mice. LD-fed Elovl6+/+Ldlr−/− mice exhibited significant reductions in epididymal white adipose tissue (WAT) weight compared with SD-fed Elovl6+/+Ldlr−/− mice (Fig. 1D). In contrast, there was no significant difference in WAT weight between LD-fed and SD-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