Human hepatocyte PNPLA3-148M exacerbates rapid non-alcoholic fatty liver disease development in chimeric mice

Mohammad Kabbani; Eleftherios Michailidis; Sandra Steensels; Clifton G. Fulmer; Joseph M. Luna; Jérémie Le Pen; Matteo Tardelli; Brandon Razooky; Inna Ricardo-Lax; Chenhui Zou; Briana Zeck; Ansgar F. Stenzel; Corrine Quirk; Lander Foquet; Alison W. Ashbrook; William M. Schneider; Serkan Belkaya; Gadi Lalazar; Yupu Liang; Meredith Pittman; Lindsey Devisscher; Hiroshi Suemizu; Neil D. Theise; Luis Chiriboga; David E. Cohen; Robert Copenhaver; Markus Grompe; Philip Meuleman; Baran A. Ersoy; Charles M. Rice; Ype P. de Jong

doi:10.1016/j.celrep.2022.111321

Human hepatocyte PNPLA3-148M exacerbates rapid non-alcoholic fatty liver disease development in chimeric mice

Mohammad Kabbani, Eleftherios Michailidis, Sandra Steensels, Clifton G. Fulmer, Joseph M. Luna, Jérémie Le Pen, Matteo Tardelli, Brandon Razooky, Inna Ricardo-Lax, Chenhui Zou, Briana Zeck, Ansgar F. Stenzel, Corrine Quirk, Lander Foquet, Alison W. Ashbrook, William M. Schneider, Serkan Belkaya, Gadi Lalazar, Yupu Liang, Meredith PittmanLindsey Devisscher, Hiroshi Suemizu, Neil D. Theise, Luis Chiriboga, David E. Cohen, Robert Copenhaver, Markus Grompe, Philip Meuleman, Baran A. Ersoy, Charles M. Rice, Ype P. de Jong

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

5 Scopus citations

Abstract

Advanced non-alcoholic fatty liver disease (NAFLD) is a rapidly emerging global health problem associated with pre-disposing genetic polymorphisms, most strikingly an isoleucine to methionine substitution in patatin-like phospholipase domain-containing protein 3 (PNPLA3-I148M). Here, we study how human hepatocytes with PNPLA3 148I and 148M variants engrafted in the livers of broadly immunodeficient chimeric mice respond to hypercaloric diets. As early as four weeks, mice developed dyslipidemia, impaired glucose tolerance, and steatosis with ballooning degeneration selectively in the human graft, followed by pericellular fibrosis after eight weeks of hypercaloric feeding. Hepatocytes with the PNPLA3-148M variant, either from a homozygous 148M donor or overexpressed in a 148I donor background, developed microvesicular and severe steatosis with frequent ballooning degeneration, resulting in more active steatohepatitis than 148I hepatocytes. We conclude that PNPLA3-148M in human hepatocytes exacerbates NAFLD. These models will facilitate mechanistic studies into human genetic variant contributions to advanced fatty liver diseases.

Original language	English (US)
Article number	111321
Journal	Cell Reports
Volume	40
Issue number	11
DOIs	https://doi.org/10.1016/j.celrep.2022.111321
State	Published - Sep 13 2022

Keywords

CP: Metabolism
NAFLD progression
NASH
human genetics
hypernutrition

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

Access to Document

10.1016/j.celrep.2022.111321

Cite this

Kabbani, M., Michailidis, E., Steensels, S., Fulmer, C. G., Luna, J. M., Le Pen, J., Tardelli, M., Razooky, B., Ricardo-Lax, I., Zou, C., Zeck, B., Stenzel, A. F., Quirk, C., Foquet, L., Ashbrook, A. W., Schneider, W. M., Belkaya, S., Lalazar, G., Liang, Y., ... de Jong, Y. P. (2022). Human hepatocyte PNPLA3-148M exacerbates rapid non-alcoholic fatty liver disease development in chimeric mice. Cell Reports, 40(11), Article 111321. https://doi.org/10.1016/j.celrep.2022.111321

Kabbani, M, Michailidis, E, Steensels, S, Fulmer, CG, Luna, JM, Le Pen, J, Tardelli, M, Razooky, B, Ricardo-Lax, I, Zou, C, Zeck, B, Stenzel, AF, Quirk, C, Foquet, L, Ashbrook, AW, Schneider, WM, Belkaya, S, Lalazar, G, Liang, Y, Pittman, M, Devisscher, L, Suemizu, H, Theise, ND, Chiriboga, L, Cohen, DE, Copenhaver, R, Grompe, M, Meuleman, P, Ersoy, BA, Rice, CM & de Jong, YP 2022, 'Human hepatocyte PNPLA3-148M exacerbates rapid non-alcoholic fatty liver disease development in chimeric mice', Cell Reports, vol. 40, no. 11, 111321. https://doi.org/10.1016/j.celrep.2022.111321

@article{e6d0573b40a2428d9e4d3f89efb7002b,

title = "Human hepatocyte PNPLA3-148M exacerbates rapid non-alcoholic fatty liver disease development in chimeric mice",

abstract = "Advanced non-alcoholic fatty liver disease (NAFLD) is a rapidly emerging global health problem associated with pre-disposing genetic polymorphisms, most strikingly an isoleucine to methionine substitution in patatin-like phospholipase domain-containing protein 3 (PNPLA3-I148M). Here, we study how human hepatocytes with PNPLA3 148I and 148M variants engrafted in the livers of broadly immunodeficient chimeric mice respond to hypercaloric diets. As early as four weeks, mice developed dyslipidemia, impaired glucose tolerance, and steatosis with ballooning degeneration selectively in the human graft, followed by pericellular fibrosis after eight weeks of hypercaloric feeding. Hepatocytes with the PNPLA3-148M variant, either from a homozygous 148M donor or overexpressed in a 148I donor background, developed microvesicular and severe steatosis with frequent ballooning degeneration, resulting in more active steatohepatitis than 148I hepatocytes. We conclude that PNPLA3-148M in human hepatocytes exacerbates NAFLD. These models will facilitate mechanistic studies into human genetic variant contributions to advanced fatty liver diseases.",

keywords = "CP: Metabolism, NAFLD progression, NASH, human genetics, hypernutrition",

author = "Mohammad Kabbani and Eleftherios Michailidis and Sandra Steensels and Fulmer, {Clifton G.} and Luna, {Joseph M.} and {Le Pen}, J{\'e}r{\'e}mie and Matteo Tardelli and Brandon Razooky and Inna Ricardo-Lax and Chenhui Zou and Briana Zeck and Stenzel, {Ansgar F.} and Corrine Quirk and Lander Foquet and Ashbrook, {Alison W.} and Schneider, {William M.} and Serkan Belkaya and Gadi Lalazar and Yupu Liang and Meredith Pittman and Lindsey Devisscher and Hiroshi Suemizu and Theise, {Neil D.} and Luis Chiriboga and Cohen, {David E.} and Robert Copenhaver and Markus Grompe and Philip Meuleman and Ersoy, {Baran A.} and Rice, {Charles M.} and {de Jong}, {Ype P.}",

note = "Publisher Copyright: {\textcopyright} 2022",

year = "2022",

month = sep,

day = "13",

doi = "10.1016/j.celrep.2022.111321",

language = "English (US)",

volume = "40",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "11",

}

TY - JOUR

T1 - Human hepatocyte PNPLA3-148M exacerbates rapid non-alcoholic fatty liver disease development in chimeric mice

AU - Kabbani, Mohammad

AU - Michailidis, Eleftherios

AU - Steensels, Sandra

AU - Fulmer, Clifton G.

AU - Luna, Joseph M.

AU - Le Pen, Jérémie

AU - Tardelli, Matteo

AU - Razooky, Brandon

AU - Ricardo-Lax, Inna

AU - Zou, Chenhui

AU - Zeck, Briana

AU - Stenzel, Ansgar F.

AU - Quirk, Corrine

AU - Foquet, Lander

AU - Ashbrook, Alison W.

AU - Schneider, William M.

AU - Belkaya, Serkan

AU - Lalazar, Gadi

AU - Liang, Yupu

AU - Pittman, Meredith

AU - Devisscher, Lindsey

AU - Suemizu, Hiroshi

AU - Theise, Neil D.

AU - Chiriboga, Luis

AU - Cohen, David E.

AU - Copenhaver, Robert

AU - Grompe, Markus

AU - Meuleman, Philip

AU - Ersoy, Baran A.

AU - Rice, Charles M.

AU - de Jong, Ype P.

PY - 2022/9/13

Y1 - 2022/9/13

N2 - Advanced non-alcoholic fatty liver disease (NAFLD) is a rapidly emerging global health problem associated with pre-disposing genetic polymorphisms, most strikingly an isoleucine to methionine substitution in patatin-like phospholipase domain-containing protein 3 (PNPLA3-I148M). Here, we study how human hepatocytes with PNPLA3 148I and 148M variants engrafted in the livers of broadly immunodeficient chimeric mice respond to hypercaloric diets. As early as four weeks, mice developed dyslipidemia, impaired glucose tolerance, and steatosis with ballooning degeneration selectively in the human graft, followed by pericellular fibrosis after eight weeks of hypercaloric feeding. Hepatocytes with the PNPLA3-148M variant, either from a homozygous 148M donor or overexpressed in a 148I donor background, developed microvesicular and severe steatosis with frequent ballooning degeneration, resulting in more active steatohepatitis than 148I hepatocytes. We conclude that PNPLA3-148M in human hepatocytes exacerbates NAFLD. These models will facilitate mechanistic studies into human genetic variant contributions to advanced fatty liver diseases.

AB - Advanced non-alcoholic fatty liver disease (NAFLD) is a rapidly emerging global health problem associated with pre-disposing genetic polymorphisms, most strikingly an isoleucine to methionine substitution in patatin-like phospholipase domain-containing protein 3 (PNPLA3-I148M). Here, we study how human hepatocytes with PNPLA3 148I and 148M variants engrafted in the livers of broadly immunodeficient chimeric mice respond to hypercaloric diets. As early as four weeks, mice developed dyslipidemia, impaired glucose tolerance, and steatosis with ballooning degeneration selectively in the human graft, followed by pericellular fibrosis after eight weeks of hypercaloric feeding. Hepatocytes with the PNPLA3-148M variant, either from a homozygous 148M donor or overexpressed in a 148I donor background, developed microvesicular and severe steatosis with frequent ballooning degeneration, resulting in more active steatohepatitis than 148I hepatocytes. We conclude that PNPLA3-148M in human hepatocytes exacerbates NAFLD. These models will facilitate mechanistic studies into human genetic variant contributions to advanced fatty liver diseases.

KW - CP: Metabolism

KW - NAFLD progression

KW - NASH

KW - human genetics

KW - hypernutrition

UR - http://www.scopus.com/inward/record.url?scp=85137876509&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85137876509&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2022.111321

DO - 10.1016/j.celrep.2022.111321

M3 - Article

C2 - 36103835

AN - SCOPUS:85137876509

SN - 2211-1247

VL - 40

JO - Cell Reports

JF - Cell Reports

IS - 11

M1 - 111321

ER -

Human hepatocyte PNPLA3-148M exacerbates rapid non-alcoholic fatty liver disease development in chimeric mice

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this