Creosote bush-derived NDGA attenuates molecular and pathological changes in a novel mouse model of non-alcoholic steatohepatitis (NASH)

Lu Han; Stefanie Bittner; Dachuan Dong; Yuan Cortez; Hunter Dulay; Sara Arshad; Wen-Jun Shen; Fredric B Kraemer; Salman Azhar

doi:10.1016/j.mce.2019.110538

Creosote bush-derived NDGA attenuates molecular and pathological changes in a novel mouse model of non-alcoholic steatohepatitis (NASH)

Mol Cell Endocrinol. 2019 Dec 1:498:110538. doi: 10.1016/j.mce.2019.110538. Epub 2019 Aug 12.

Authors

Lu Han¹, Stefanie Bittner², Dachuan Dong¹, Yuan Cortez², Hunter Dulay², Sara Arshad¹, Wen-Jun Shen³, Fredric B Kraemer⁴, Salman Azhar⁵

Affiliations

¹ Geriatric Research, Education and Clinical Center, VA Palo Alto Health Care System, CA, USA; Division of Endocrinology, Gerontology and Metabolism, Stanford University, Stanford, CA, USA.
² Geriatric Research, Education and Clinical Center, VA Palo Alto Health Care System, CA, USA.
³ Geriatric Research, Education and Clinical Center, VA Palo Alto Health Care System, CA, USA; Division of Endocrinology, Gerontology and Metabolism, Stanford University, Stanford, CA, USA. Electronic address: wenjun@stanford.edu.
⁴ Geriatric Research, Education and Clinical Center, VA Palo Alto Health Care System, CA, USA; Division of Endocrinology, Gerontology and Metabolism, Stanford University, Stanford, CA, USA; Stanford Diabetes Research Center, USA.
⁵ Geriatric Research, Education and Clinical Center, VA Palo Alto Health Care System, CA, USA; Division of Endocrinology, Gerontology and Metabolism, Stanford University, Stanford, CA, USA; Stanford Diabetes Research Center, USA. Electronic address: salman.azhar@va.gov.

Abstract

Creosote bush (Larrea tridentata)-derived nordihydroguaiaretic acid (NDGA) was shown to have profound effects on the core components of metabolic syndrome. This study investigated the in vivo potential of NDGA for prevention or attenuation of the pathophysiologic abnormalities of NASH. A novel dietary NASH model with feeding C57BL/6J mice with a high trans-fat, high cholesterol and high fructose (HTF) diet, was used. The HTF diet fed mice exhibited obesity, insulin resistance, hepatic steatosis, fibrosis, inflammation, ER stress, oxidative stress, and liver injury. NDGA attenuated these metabolic abnormalities as well as hepatic steatosis and fibrosis together with attenuated expression of genes encoding fibrosis, progenitor and macrophage markers with no effect on the levels of mRNAs for lipogenic enzymes. NDGA increased expression of fatty acid oxidation genes. In conclusion, NDGA exerts anti-NASH/anti-fibrotic actions and raises the therapeutic potential of NDGA for treatment of NASH patients with fibrosis and other associated complications.

Keywords: Hepatic fibrosis; Hepatic steatosis; Insulin resistance; Metabolic syndrome; NAFLD; Nordihydroguaiaretic acid.

Publication types

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

MeSH terms

Animals
Antioxidants / pharmacology
Diet, High-Fat / adverse effects*
Disease Models, Animal
Hyperlipidemias / etiology
Hyperlipidemias / metabolism
Hyperlipidemias / pathology
Hyperlipidemias / prevention & control*
Inflammation / etiology
Inflammation / metabolism
Inflammation / pathology
Inflammation / prevention & control*
Insulin Resistance*
Larrea / chemistry
Lipogenesis / drug effects
Male
Masoprocol / pharmacology*
Mice
Mice, Inbred C57BL
Non-alcoholic Fatty Liver Disease / drug therapy*
Non-alcoholic Fatty Liver Disease / etiology
Non-alcoholic Fatty Liver Disease / metabolism
Non-alcoholic Fatty Liver Disease / pathology
Obesity / etiology
Obesity / metabolism
Obesity / pathology
Obesity / prevention & control*
Oxidative Stress / drug effects

Substances

Antioxidants
Masoprocol

Abstract

Publication types

MeSH terms

Substances

Grants and funding