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Is Western Diet-Induced Nonalcoholic Steatohepatitis in Ldlr-/- Mice Reversible?
PLoS One. 2016; 11(1):e0146942.Plos

Abstract

BACKGROUND

Nonalcoholic fatty liver disease (NAFLD) is a major public health burden in western societies. The progressive form of NAFLD, nonalcoholic steatohepatitis (NASH), is characterized by hepatosteatosis, inflammation, oxidative stress, and hepatic damage that can progress to fibrosis and cirrhosis; risk factors for hepatocellular carcinoma. Given the scope of NASH, validating treatment protocols (i.e., low fat diets and weight loss) is imperative.

METHODS

We evaluated the efficacy of two diets, a non-purified chow (NP) and purified (low-fat low-cholesterol, LFLC) diet to reverse western diet (WD)-induced NASH and fibrosis in Ldlr-/- mice.

RESULTS

Mice fed WD for 22-24 weeks developed robust hepatosteatosis with mild fibrosis, while mice maintained on the WD an additional 7-8 weeks developed NASH with moderate fibrosis. Returning WD-fed mice to the NP or LFLC diets significantly reduced body weight and plasma markers of metabolic syndrome (dyslipidemia, hyperglycemia) and hepatic gene expression markers of inflammation (Mcp1), oxidative stress (Nox2), fibrosis (Col1A, LoxL2, Timp1) and collagen crosslinking (hydroxyproline). Time course analyses established that plasma triglycerides and hepatic Col1A1 mRNA were rapidly reduced following the switch from the WD to the LFLC diet. However, hepatic triglyceride content and fibrosis did not return to normal levels 8 weeks after the change to the LFLC diet. Time course studies further revealed a strong association (r2 ≥ 0.52) between plasma markers of inflammation (TLR2 activators) and hepatic fibrosis markers (Col1A, Timp1, LoxL2). Inflammation and fibrosis markers were inversely associated (r2 ≥ 0.32) with diet-induced changes in hepatic ω3 and ω6 polyunsaturated fatty acids (PUFA) content.

CONCLUSION

These studies establish a temporal link between plasma markers of inflammation and hepatic PUFA and fibrosis. Low-fat low-cholesterol diets promote reversal of many, but not all, features associated with WD-induced NASH and fibrosis in Ldlr-/- mice.

Authors+Show Affiliations

Nutrition Program, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon, United States of America. Linus Pauling Institute, Oregon State University, Corvallis, Oregon, United States of America.Nutrition Program, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon, United States of America. Linus Pauling Institute, Oregon State University, Corvallis, Oregon, United States of America.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

26761430

Citation

Lytle, Kelli A., and Donald B. Jump. "Is Western Diet-Induced Nonalcoholic Steatohepatitis in Ldlr-/- Mice Reversible?" PloS One, vol. 11, no. 1, 2016, pp. e0146942.
Lytle KA, Jump DB. Is Western Diet-Induced Nonalcoholic Steatohepatitis in Ldlr-/- Mice Reversible? PLoS ONE. 2016;11(1):e0146942.
Lytle, K. A., & Jump, D. B. (2016). Is Western Diet-Induced Nonalcoholic Steatohepatitis in Ldlr-/- Mice Reversible? PloS One, 11(1), e0146942. https://doi.org/10.1371/journal.pone.0146942
Lytle KA, Jump DB. Is Western Diet-Induced Nonalcoholic Steatohepatitis in Ldlr-/- Mice Reversible. PLoS ONE. 2016;11(1):e0146942. PubMed PMID: 26761430.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Is Western Diet-Induced Nonalcoholic Steatohepatitis in Ldlr-/- Mice Reversible? AU - Lytle,Kelli A, AU - Jump,Donald B, Y1 - 2016/01/13/ PY - 2015/10/20/received PY - 2015/12/26/accepted PY - 2016/1/14/entrez PY - 2016/1/14/pubmed PY - 2016/7/9/medline SP - e0146942 EP - e0146942 JF - PloS one JO - PLoS ONE VL - 11 IS - 1 N2 - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a major public health burden in western societies. The progressive form of NAFLD, nonalcoholic steatohepatitis (NASH), is characterized by hepatosteatosis, inflammation, oxidative stress, and hepatic damage that can progress to fibrosis and cirrhosis; risk factors for hepatocellular carcinoma. Given the scope of NASH, validating treatment protocols (i.e., low fat diets and weight loss) is imperative. METHODS: We evaluated the efficacy of two diets, a non-purified chow (NP) and purified (low-fat low-cholesterol, LFLC) diet to reverse western diet (WD)-induced NASH and fibrosis in Ldlr-/- mice. RESULTS: Mice fed WD for 22-24 weeks developed robust hepatosteatosis with mild fibrosis, while mice maintained on the WD an additional 7-8 weeks developed NASH with moderate fibrosis. Returning WD-fed mice to the NP or LFLC diets significantly reduced body weight and plasma markers of metabolic syndrome (dyslipidemia, hyperglycemia) and hepatic gene expression markers of inflammation (Mcp1), oxidative stress (Nox2), fibrosis (Col1A, LoxL2, Timp1) and collagen crosslinking (hydroxyproline). Time course analyses established that plasma triglycerides and hepatic Col1A1 mRNA were rapidly reduced following the switch from the WD to the LFLC diet. However, hepatic triglyceride content and fibrosis did not return to normal levels 8 weeks after the change to the LFLC diet. Time course studies further revealed a strong association (r2 ≥ 0.52) between plasma markers of inflammation (TLR2 activators) and hepatic fibrosis markers (Col1A, Timp1, LoxL2). Inflammation and fibrosis markers were inversely associated (r2 ≥ 0.32) with diet-induced changes in hepatic ω3 and ω6 polyunsaturated fatty acids (PUFA) content. CONCLUSION: These studies establish a temporal link between plasma markers of inflammation and hepatic PUFA and fibrosis. Low-fat low-cholesterol diets promote reversal of many, but not all, features associated with WD-induced NASH and fibrosis in Ldlr-/- mice. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/26761430/Is_Western_Diet_Induced_Nonalcoholic_Steatohepatitis_in_Ldlr_/__Mice_Reversible L2 - http://dx.plos.org/10.1371/journal.pone.0146942 DB - PRIME DP - Unbound Medicine ER -