SMN Depleted Mice Offer a Robust and Rapid Onset Model of Nonalcoholic Fatty Liver Disease

Marc-Olivier Deguise; Chantal Pileggi; Yves De Repentigny; Ariane Beauvais; Alexandra Tierney; Lucia Chehade; Jean Michaud; Maica Llavero-Hurtado; Douglas Lamont; Abdelmadjid Atrih; Thomas M Wishart; Thomas H Gillingwater; Bernard L Schneider; Mary-Ellen Harper; Simon H Parson; Rashmi Kothary

doi:10.1016/j.jcmgh.2021.01.019

SMN Depleted Mice Offer a Robust and Rapid Onset Model of Nonalcoholic Fatty Liver Disease

Marc-Olivier Deguise, Chantal Pileggi, Yves De Repentigny, Ariane Beauvais, Alexandra Tierney, Lucia Chehade, Jean Michaud, Maica Llavero-Hurtado, Douglas Lamont, Abdelmadjid Atrih, Thomas M Wishart, Thomas H Gillingwater, Bernard L Schneider, Mary-Ellen Harper, Simon H Parson, Rashmi Kothary^* (Corresponding Author)

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is considered a health epidemic with potential devastating effects on the patients and the healthcare systems. Current preclinical models of NAFLD are invariably imperfect and generally take a long time to develop. A mouse model of survival motor neuron (SMN) depletion (Smn2B/- mice) was recently shown to develop significant hepatic steatosis in less than 2 weeks from birth. The rapid onset of fatty liver in Smn2B/- mice provides an opportunity to identify molecular markers of NAFLD. Here, we investigated whether Smn2B/- mice display typical features of NAFLD/nonalcoholic steatohepatitis (NASH).

METHODS: Biochemical, histologic, electron microscopy, proteomic, and high-resolution respirometry were used.

RESULTS: The Smn2B/- mice develop microvesicular steatohepatitis within 2 weeks, a feature prevented by AAV9-SMN gene therapy. Although fibrosis is not overtly apparent in histologic sections of the liver, there is molecular evidence of fibrogenesis and presence of stellate cell activation. The consequent liver damage arises from mitochondrial reactive oxygen species production and results in hepatic dysfunction in protein output, complement, coagulation, iron homeostasis, and insulin-like growth factor-1 metabolism. The NAFLD phenotype is likely due to nonesterified fatty acid overload from peripheral lipolysis subsequent to hyperglucagonemia compounded by reduced muscle use and insulin resistance. Despite the low hepatic mitochondrial content, isolated mitochondria show enhanced β-oxidation, likely as a compensatory response, resulting in the production of reactive oxygen species. In contrast to typical NAFLD/NASH, the Smn2B/- mice lose weight because of their associated neurological condition (spinal muscular atrophy) and develop hypoglycemia.

CONCLUSIONS: The Smn2B/- mice represent a good model of microvesicular steatohepatitis. Like other models, it is not representative of the complete NAFLD/NASH spectrum. Nevertheless, it offers a reliable, low-cost, early-onset model that is not dependent on diet to identify molecular players in NAFLD pathogenesis and can serve as one of the very few models of microvesicular steatohepatitis for both adult and pediatric populations.

Original language	English
Pages (from-to)	354-377
Number of pages	27
Journal	CMGH Cellular and Molecular Gastroenterology and Hepatology
Volume	12
Issue number	1
Early online date	2 Feb 2021
DOIs	https://doi.org/10.1016/j.jcmgh.2021.01.019
Publication status	Published - 2021

Bibliographical note

Acknowledgments
The authors thank Eva Szunyogova, Sabrina Gagnon, My Tran Trung, andRebecca Yaworski, the Vanderbilt Mouse Metabolic Phenotyping Center, and the University of Massachusetts Medical School National Mouse Metabolic Phenotyping Center (MMPC) for assistance with experiments. They also thank Dr Lyndsay Murray for providing some tissues for the present study.

Keywords

SMN
NAFLD
NASH
Metabolism

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Deguise, M.-O., Pileggi, C., De Repentigny, Y., Beauvais, A., Tierney, A., Chehade, L., Michaud, J., Llavero-Hurtado, M., Lamont, D., Atrih, A., Wishart, T. M., Gillingwater, T. H., Schneider, B. L., Harper, M.-E., Parson, S. H., & Kothary, R. (2021). SMN Depleted Mice Offer a Robust and Rapid Onset Model of Nonalcoholic Fatty Liver Disease. CMGH Cellular and Molecular Gastroenterology and Hepatology, 12(1), 354-377. https://doi.org/10.1016/j.jcmgh.2021.01.019

Deguise, M-O, Pileggi, C, De Repentigny, Y, Beauvais, A, Tierney, A, Chehade, L, Michaud, J, Llavero-Hurtado, M, Lamont, D, Atrih, A, Wishart, TM, Gillingwater, TH, Schneider, BL, Harper, M-E, Parson, SH & Kothary, R 2021, 'SMN Depleted Mice Offer a Robust and Rapid Onset Model of Nonalcoholic Fatty Liver Disease', CMGH Cellular and Molecular Gastroenterology and Hepatology, vol. 12, no. 1, pp. 354-377. https://doi.org/10.1016/j.jcmgh.2021.01.019

@article{4444aa752a1c44e6b5e8b38dddc1afb1,

title = "SMN Depleted Mice Offer a Robust and Rapid Onset Model of Nonalcoholic Fatty Liver Disease",

abstract = "BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is considered a health epidemic with potential devastating effects on the patients and the healthcare systems. Current preclinical models of NAFLD are invariably imperfect and generally take a long time to develop. A mouse model of survival motor neuron (SMN) depletion (Smn2B/- mice) was recently shown to develop significant hepatic steatosis in less than 2 weeks from birth. The rapid onset of fatty liver in Smn2B/- mice provides an opportunity to identify molecular markers of NAFLD. Here, we investigated whether Smn2B/- mice display typical features of NAFLD/nonalcoholic steatohepatitis (NASH).METHODS: Biochemical, histologic, electron microscopy, proteomic, and high-resolution respirometry were used.RESULTS: The Smn2B/- mice develop microvesicular steatohepatitis within 2 weeks, a feature prevented by AAV9-SMN gene therapy. Although fibrosis is not overtly apparent in histologic sections of the liver, there is molecular evidence of fibrogenesis and presence of stellate cell activation. The consequent liver damage arises from mitochondrial reactive oxygen species production and results in hepatic dysfunction in protein output, complement, coagulation, iron homeostasis, and insulin-like growth factor-1 metabolism. The NAFLD phenotype is likely due to nonesterified fatty acid overload from peripheral lipolysis subsequent to hyperglucagonemia compounded by reduced muscle use and insulin resistance. Despite the low hepatic mitochondrial content, isolated mitochondria show enhanced β-oxidation, likely as a compensatory response, resulting in the production of reactive oxygen species. In contrast to typical NAFLD/NASH, the Smn2B/- mice lose weight because of their associated neurological condition (spinal muscular atrophy) and develop hypoglycemia.CONCLUSIONS: The Smn2B/- mice represent a good model of microvesicular steatohepatitis. Like other models, it is not representative of the complete NAFLD/NASH spectrum. Nevertheless, it offers a reliable, low-cost, early-onset model that is not dependent on diet to identify molecular players in NAFLD pathogenesis and can serve as one of the very few models of microvesicular steatohepatitis for both adult and pediatric populations.",

keywords = "SMN, NAFLD, NASH, Metabolism",

author = "Marc-Olivier Deguise and Chantal Pileggi and {De Repentigny}, Yves and Ariane Beauvais and Alexandra Tierney and Lucia Chehade and Jean Michaud and Maica Llavero-Hurtado and Douglas Lamont and Abdelmadjid Atrih and Wishart, {Thomas M} and Gillingwater, {Thomas H} and Schneider, {Bernard L} and Mary-Ellen Harper and Parson, {Simon H} and Rashmi Kothary",

note = "Acknowledgments The authors thank Eva Szunyogova, Sabrina Gagnon, My Tran Trung, andRebecca Yaworski, the Vanderbilt Mouse Metabolic Phenotyping Center, and the University of Massachusetts Medical School National Mouse Metabolic Phenotyping Center (MMPC) for assistance with experiments. They also thank Dr Lyndsay Murray for providing some tissues for the present study.",

year = "2021",

doi = "10.1016/j.jcmgh.2021.01.019",

language = "English",

volume = "12",

pages = "354--377",

journal = "CMGH Cellular and Molecular Gastroenterology and Hepatology",

issn = "2352-345X",

publisher = "Elsevier Inc.",

number = "1",

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TY - JOUR

T1 - SMN Depleted Mice Offer a Robust and Rapid Onset Model of Nonalcoholic Fatty Liver Disease

AU - Deguise, Marc-Olivier

AU - Pileggi, Chantal

AU - De Repentigny, Yves

AU - Beauvais, Ariane

AU - Tierney, Alexandra

AU - Chehade, Lucia

AU - Michaud, Jean

AU - Llavero-Hurtado, Maica

AU - Lamont, Douglas

AU - Atrih, Abdelmadjid

AU - Wishart, Thomas M

AU - Gillingwater, Thomas H

AU - Schneider, Bernard L

AU - Harper, Mary-Ellen

AU - Parson, Simon H

AU - Kothary, Rashmi

N1 - Acknowledgments The authors thank Eva Szunyogova, Sabrina Gagnon, My Tran Trung, andRebecca Yaworski, the Vanderbilt Mouse Metabolic Phenotyping Center, and the University of Massachusetts Medical School National Mouse Metabolic Phenotyping Center (MMPC) for assistance with experiments. They also thank Dr Lyndsay Murray for providing some tissues for the present study.

PY - 2021

Y1 - 2021

N2 - BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is considered a health epidemic with potential devastating effects on the patients and the healthcare systems. Current preclinical models of NAFLD are invariably imperfect and generally take a long time to develop. A mouse model of survival motor neuron (SMN) depletion (Smn2B/- mice) was recently shown to develop significant hepatic steatosis in less than 2 weeks from birth. The rapid onset of fatty liver in Smn2B/- mice provides an opportunity to identify molecular markers of NAFLD. Here, we investigated whether Smn2B/- mice display typical features of NAFLD/nonalcoholic steatohepatitis (NASH).METHODS: Biochemical, histologic, electron microscopy, proteomic, and high-resolution respirometry were used.RESULTS: The Smn2B/- mice develop microvesicular steatohepatitis within 2 weeks, a feature prevented by AAV9-SMN gene therapy. Although fibrosis is not overtly apparent in histologic sections of the liver, there is molecular evidence of fibrogenesis and presence of stellate cell activation. The consequent liver damage arises from mitochondrial reactive oxygen species production and results in hepatic dysfunction in protein output, complement, coagulation, iron homeostasis, and insulin-like growth factor-1 metabolism. The NAFLD phenotype is likely due to nonesterified fatty acid overload from peripheral lipolysis subsequent to hyperglucagonemia compounded by reduced muscle use and insulin resistance. Despite the low hepatic mitochondrial content, isolated mitochondria show enhanced β-oxidation, likely as a compensatory response, resulting in the production of reactive oxygen species. In contrast to typical NAFLD/NASH, the Smn2B/- mice lose weight because of their associated neurological condition (spinal muscular atrophy) and develop hypoglycemia.CONCLUSIONS: The Smn2B/- mice represent a good model of microvesicular steatohepatitis. Like other models, it is not representative of the complete NAFLD/NASH spectrum. Nevertheless, it offers a reliable, low-cost, early-onset model that is not dependent on diet to identify molecular players in NAFLD pathogenesis and can serve as one of the very few models of microvesicular steatohepatitis for both adult and pediatric populations.

AB - BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is considered a health epidemic with potential devastating effects on the patients and the healthcare systems. Current preclinical models of NAFLD are invariably imperfect and generally take a long time to develop. A mouse model of survival motor neuron (SMN) depletion (Smn2B/- mice) was recently shown to develop significant hepatic steatosis in less than 2 weeks from birth. The rapid onset of fatty liver in Smn2B/- mice provides an opportunity to identify molecular markers of NAFLD. Here, we investigated whether Smn2B/- mice display typical features of NAFLD/nonalcoholic steatohepatitis (NASH).METHODS: Biochemical, histologic, electron microscopy, proteomic, and high-resolution respirometry were used.RESULTS: The Smn2B/- mice develop microvesicular steatohepatitis within 2 weeks, a feature prevented by AAV9-SMN gene therapy. Although fibrosis is not overtly apparent in histologic sections of the liver, there is molecular evidence of fibrogenesis and presence of stellate cell activation. The consequent liver damage arises from mitochondrial reactive oxygen species production and results in hepatic dysfunction in protein output, complement, coagulation, iron homeostasis, and insulin-like growth factor-1 metabolism. The NAFLD phenotype is likely due to nonesterified fatty acid overload from peripheral lipolysis subsequent to hyperglucagonemia compounded by reduced muscle use and insulin resistance. Despite the low hepatic mitochondrial content, isolated mitochondria show enhanced β-oxidation, likely as a compensatory response, resulting in the production of reactive oxygen species. In contrast to typical NAFLD/NASH, the Smn2B/- mice lose weight because of their associated neurological condition (spinal muscular atrophy) and develop hypoglycemia.CONCLUSIONS: The Smn2B/- mice represent a good model of microvesicular steatohepatitis. Like other models, it is not representative of the complete NAFLD/NASH spectrum. Nevertheless, it offers a reliable, low-cost, early-onset model that is not dependent on diet to identify molecular players in NAFLD pathogenesis and can serve as one of the very few models of microvesicular steatohepatitis for both adult and pediatric populations.

KW - SMN

KW - NAFLD

KW - NASH

KW - Metabolism

U2 - 10.1016/j.jcmgh.2021.01.019

DO - 10.1016/j.jcmgh.2021.01.019

M3 - Article

C2 - 33545428

SN - 2352-345X

VL - 12

SP - 354

EP - 377

JO - CMGH Cellular and Molecular Gastroenterology and Hepatology

JF - CMGH Cellular and Molecular Gastroenterology and Hepatology

IS - 1

ER -

SMN Depleted Mice Offer a Robust and Rapid Onset Model of Nonalcoholic Fatty Liver Disease

Abstract

Bibliographical note

Keywords

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