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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

Elovl6 deficiency suppresses lithogenic diet (LD)-induced hepatic lipid accumulation in Ldlr−/− mice.(A) Representative photographs of livers from Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice fed an LD for 4 weeks. (B) The prevalence rate of gallstones in Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice fed an LD for 4 weeks (n = 8–10 per group). (C) Polarizing light microscopy of gallbladder bile from Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice fed an LD for 4 weeks (magnification, ×200). (D–F) Hepatic total cholesterol (TC) (D), triglyceride (TG) (E) and total bile acid (TBA) (F) levels in Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice fed a standard diet (SD) or an LD for 4 weeks (n = 8–13 per group). *P < 0.05, **P < 0.01.
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f3: Elovl6 deficiency suppresses lithogenic diet (LD)-induced hepatic lipid accumulation in Ldlr−/− mice.(A) Representative photographs of livers from Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice fed an LD for 4 weeks. (B) The prevalence rate of gallstones in Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice fed an LD for 4 weeks (n = 8–10 per group). (C) Polarizing light microscopy of gallbladder bile from Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice fed an LD for 4 weeks (magnification, ×200). (D–F) Hepatic total cholesterol (TC) (D), triglyceride (TG) (E) and total bile acid (TBA) (F) levels in Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice fed a standard diet (SD) or an LD for 4 weeks (n = 8–13 per group). *P < 0.05, **P < 0.01.

Mentions: Photographs of the opened abdominal cavities of both groups on the LD show that the livers of LD-fed Elovl6+/+Ldlr−/− mice were pale, but the livers of LD-fed Elovl6−/−Ldlr−/− mice were red (Fig. 3A). However, in contrast to Elovl6+/+Ldlr−/− mice after 4 weeks of the LD, the LD-fed Elovl6−/−Ldlr−/− mice had opaque gallbladders and increased numbers of aggregated cholesterol gallstones in greenish bile. The incidence of gallstones was higher in Elovl6−/−Ldlr−/− mice (80%) than in Elovl6+/+Ldlr−/− mice (37.5%) after 4-week feeding of LD (Fig. 3B). Microscopic examination of the gallbladder bile from LD-fed Elovl6−/−Ldlr−/− mice revealed numerous large cholesterol monohydrate crystals; whereas, bile from LD-fed Elovl6+/+Ldlr−/− mice was largely free of cholesterol precipitates, with only occasional aggregated vesicles in most animals (Fig. 3C). The LD markedly increased liver TC and increased liver TG levels in Elovl6+/+Ldlr−/− mice. In LD-fed Elovl6−/−Ldlr−/− mice, the liver TC increase was reduced to half that observed in Elovl6+/+Ldlr−/− mice and there was no increase in TG levels (Fig. 3D, E). The LD increased liver TBA levels in both genotypes, but unlike plasma levels, there was no significant difference between the groups (Fig. 3F). Bile TC, TBA, phospholipid (PL), faecal TC and TBA levels were similar between LD-fed Elovl6+/+Ldlr−/− and LD-fed Elovl6−/−Ldlr−/− mice (see Supplementary Fig. S1 online). These results suggest that it was the change in hepatic lipid metabolism in LD-fed Elovl6−/−Ldlr−/− mice that suppressed hepatic cholesterol and triglycerides accumulation and enhanced gallstone formation, rather than a functional change in the gallbladder or intestine.


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)

Elovl6 deficiency suppresses lithogenic diet (LD)-induced hepatic lipid accumulation in Ldlr−/− mice.(A) Representative photographs of livers from Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice fed an LD for 4 weeks. (B) The prevalence rate of gallstones in Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice fed an LD for 4 weeks (n = 8–10 per group). (C) Polarizing light microscopy of gallbladder bile from Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice fed an LD for 4 weeks (magnification, ×200). (D–F) Hepatic total cholesterol (TC) (D), triglyceride (TG) (E) and total bile acid (TBA) (F) levels in Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice fed a standard diet (SD) or an 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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getmorefigures.php?uid=PMC4664962&req=5

f3: Elovl6 deficiency suppresses lithogenic diet (LD)-induced hepatic lipid accumulation in Ldlr−/− mice.(A) Representative photographs of livers from Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice fed an LD for 4 weeks. (B) The prevalence rate of gallstones in Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice fed an LD for 4 weeks (n = 8–10 per group). (C) Polarizing light microscopy of gallbladder bile from Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice fed an LD for 4 weeks (magnification, ×200). (D–F) Hepatic total cholesterol (TC) (D), triglyceride (TG) (E) and total bile acid (TBA) (F) levels in Elovl6+/+Ldlr−/− and Elovl6−/−Ldlr−/− mice fed a standard diet (SD) or an LD for 4 weeks (n = 8–13 per group). *P < 0.05, **P < 0.01.
Mentions: Photographs of the opened abdominal cavities of both groups on the LD show that the livers of LD-fed Elovl6+/+Ldlr−/− mice were pale, but the livers of LD-fed Elovl6−/−Ldlr−/− mice were red (Fig. 3A). However, in contrast to Elovl6+/+Ldlr−/− mice after 4 weeks of the LD, the LD-fed Elovl6−/−Ldlr−/− mice had opaque gallbladders and increased numbers of aggregated cholesterol gallstones in greenish bile. The incidence of gallstones was higher in Elovl6−/−Ldlr−/− mice (80%) than in Elovl6+/+Ldlr−/− mice (37.5%) after 4-week feeding of LD (Fig. 3B). Microscopic examination of the gallbladder bile from LD-fed Elovl6−/−Ldlr−/− mice revealed numerous large cholesterol monohydrate crystals; whereas, bile from LD-fed Elovl6+/+Ldlr−/− mice was largely free of cholesterol precipitates, with only occasional aggregated vesicles in most animals (Fig. 3C). The LD markedly increased liver TC and increased liver TG levels in Elovl6+/+Ldlr−/− mice. In LD-fed Elovl6−/−Ldlr−/− mice, the liver TC increase was reduced to half that observed in Elovl6+/+Ldlr−/− mice and there was no increase in TG levels (Fig. 3D, E). The LD increased liver TBA levels in both genotypes, but unlike plasma levels, there was no significant difference between the groups (Fig. 3F). Bile TC, TBA, phospholipid (PL), faecal TC and TBA levels were similar between LD-fed Elovl6+/+Ldlr−/− and LD-fed Elovl6−/−Ldlr−/− mice (see Supplementary Fig. S1 online). These results suggest that it was the change in hepatic lipid metabolism in LD-fed Elovl6−/−Ldlr−/− mice that suppressed hepatic cholesterol and triglycerides accumulation and enhanced gallstone formation, rather than a functional change in the gallbladder or intestine.

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