Pleiotropic actions of IP6K1 mediate hepatic metabolic dysfunction to promote nonalcoholic fatty liver disease and steatohepatitis

Sandip Mukherjee; Molee Chakraborty; Barbara Ulmasov; Kyle McCommis; Jinsong Zhang; Danielle Carpenter; Eliwaza Naomi Msengi; Jake Haubner; Chun Guo; Daniel P. Pike; Sarbani Ghoshal; David A. Ford; Brent A. Neuschwander-Tetri; Anutosh Chakraborty

doi:10.1016/j.molmet.2021.101364

Pleiotropic actions of IP6K1 mediate hepatic metabolic dysfunction to promote nonalcoholic fatty liver disease and steatohepatitis

Sandip Mukherjee, Molee Chakraborty, Barbara Ulmasov, Kyle McCommis, Jinsong Zhang, Danielle Carpenter, Eliwaza Naomi Msengi, Jake Haubner, Chun Guo, Daniel P. Pike, Sarbani Ghoshal, David A. Ford, Brent A. Neuschwander-Tetri, Anutosh Chakraborty

Division of Nutritional Science & Obesity Medicine

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

13 Scopus citations

Abstract

Objective: Obesity and insulin resistance greatly increase the risk of nonalcoholic fatty liver disease and steatohepatitis (NAFLD/NASH). We have previously discovered that whole-body and adipocyte-specific Ip6k1deletion protects mice from high-fat-diet-induced obesity and insulin resistance due to improved adipocyte thermogenesis and insulin signaling. Here, we aimed to determine the impact of hepatocyte-specific and whole-body Ip6k1 deletion (HKO and Ip6k1-KO or KO) on liver metabolism and NAFLD/NASH. Methods: Body weight and composition; energy expenditure; glycemic profiles; and serum and liver metabolic, inflammatory, fibrotic and toxicity parameters were assessed in mice fed Western and high-fructose diet (HFrD) (WD: 40% kcal fat, 1.25% cholesterol, no added choline and HFrD: 60% kcal fructose). Mitochondrial oxidative capacity was evaluated in isolated hepatocytes. RNA-Seq was performed in liver samples. Livers from human NASH patients were analyzed by immunoblotting and mass spectrometry. Results: HKO mice displayed increased hepatocyte mitochondrial oxidative capacity and improved insulin sensitivity but were not resistant to body weight gain. Improved hepatocyte metabolism partially protected HKO mice from NAFLD/NASH. In contrast, enhanced whole-body metabolism and reduced body fat accumulation significantly protected whole-body Ip6k1-KO mice from NAFLD/NASH. Mitochondrial oxidative pathways were upregulated, whereas gluconeogenic and fibrogenic pathways were downregulated in Ip6k1-KO livers. Furthermore, IP6K1 was upregulated in human NASH livers and interacted with the enzyme O-GlcNAcase that reduces protein O-GlcNAcylation. Protein O-GlcNAcylation was found to be reduced in Ip6k1-KO and HKO mouse livers. Conclusion: Pleiotropic actions of IP6K1 in the liver and other metabolic tissues mediate hepatic metabolic dysfunction and NAFLD/NASH, and thus IP6K1 deletion may be a potential treatment target for this disease.

Original language	English
Article number	101364
Journal	Molecular Metabolism
Volume	54
DOIs	https://doi.org/10.1016/j.molmet.2021.101364
State	Published - Dec 2021

Keywords

Hyperglycemia
IP6K1
Liver
Metabolism
NAFLD/NASH
O-GlcNAcylation

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Mukherjee, S., Chakraborty, M., Ulmasov, B., McCommis, K., Zhang, J., Carpenter, D., Msengi, E. N., Haubner, J., Guo, C., Pike, D. P., Ghoshal, S., Ford, D. A., Neuschwander-Tetri, B. A., & Chakraborty, A. (2021). Pleiotropic actions of IP6K1 mediate hepatic metabolic dysfunction to promote nonalcoholic fatty liver disease and steatohepatitis. Molecular Metabolism, 54, Article 101364. https://doi.org/10.1016/j.molmet.2021.101364

@article{04befb5439984a10bd265e02e7421af6,

title = "Pleiotropic actions of IP6K1 mediate hepatic metabolic dysfunction to promote nonalcoholic fatty liver disease and steatohepatitis",

abstract = "Objective: Obesity and insulin resistance greatly increase the risk of nonalcoholic fatty liver disease and steatohepatitis (NAFLD/NASH). We have previously discovered that whole-body and adipocyte-specific Ip6k1deletion protects mice from high-fat-diet-induced obesity and insulin resistance due to improved adipocyte thermogenesis and insulin signaling. Here, we aimed to determine the impact of hepatocyte-specific and whole-body Ip6k1 deletion (HKO and Ip6k1-KO or KO) on liver metabolism and NAFLD/NASH. Methods: Body weight and composition; energy expenditure; glycemic profiles; and serum and liver metabolic, inflammatory, fibrotic and toxicity parameters were assessed in mice fed Western and high-fructose diet (HFrD) (WD: 40% kcal fat, 1.25% cholesterol, no added choline and HFrD: 60% kcal fructose). Mitochondrial oxidative capacity was evaluated in isolated hepatocytes. RNA-Seq was performed in liver samples. Livers from human NASH patients were analyzed by immunoblotting and mass spectrometry. Results: HKO mice displayed increased hepatocyte mitochondrial oxidative capacity and improved insulin sensitivity but were not resistant to body weight gain. Improved hepatocyte metabolism partially protected HKO mice from NAFLD/NASH. In contrast, enhanced whole-body metabolism and reduced body fat accumulation significantly protected whole-body Ip6k1-KO mice from NAFLD/NASH. Mitochondrial oxidative pathways were upregulated, whereas gluconeogenic and fibrogenic pathways were downregulated in Ip6k1-KO livers. Furthermore, IP6K1 was upregulated in human NASH livers and interacted with the enzyme O-GlcNAcase that reduces protein O-GlcNAcylation. Protein O-GlcNAcylation was found to be reduced in Ip6k1-KO and HKO mouse livers. Conclusion: Pleiotropic actions of IP6K1 in the liver and other metabolic tissues mediate hepatic metabolic dysfunction and NAFLD/NASH, and thus IP6K1 deletion may be a potential treatment target for this disease.",

keywords = "Hyperglycemia, IP6K1, Liver, Metabolism, NAFLD/NASH, O-GlcNAcylation",

author = "Sandip Mukherjee and Molee Chakraborty and Barbara Ulmasov and Kyle McCommis and Jinsong Zhang and Danielle Carpenter and Msengi, {Eliwaza Naomi} and Jake Haubner and Chun Guo and Pike, {Daniel P.} and Sarbani Ghoshal and Ford, {David A.} and Neuschwander-Tetri, {Brent A.} and Anutosh Chakraborty",

note = "Publisher Copyright: {\textcopyright} 2021 The Author(s)",

year = "2021",

month = dec,

doi = "10.1016/j.molmet.2021.101364",

language = "English",

volume = "54",

journal = "Molecular Metabolism",

issn = "2212-8778",

}

Mukherjee, S, Chakraborty, M, Ulmasov, B, McCommis, K, Zhang, J, Carpenter, D, Msengi, EN, Haubner, J, Guo, C, Pike, DP, Ghoshal, S, Ford, DA, Neuschwander-Tetri, BA & Chakraborty, A 2021, 'Pleiotropic actions of IP6K1 mediate hepatic metabolic dysfunction to promote nonalcoholic fatty liver disease and steatohepatitis', Molecular Metabolism, vol. 54, 101364. https://doi.org/10.1016/j.molmet.2021.101364

TY - JOUR

T1 - Pleiotropic actions of IP6K1 mediate hepatic metabolic dysfunction to promote nonalcoholic fatty liver disease and steatohepatitis

AU - Mukherjee, Sandip

AU - Chakraborty, Molee

AU - Ulmasov, Barbara

AU - McCommis, Kyle

AU - Zhang, Jinsong

AU - Carpenter, Danielle

AU - Msengi, Eliwaza Naomi

AU - Haubner, Jake

AU - Guo, Chun

AU - Pike, Daniel P.

AU - Ghoshal, Sarbani

AU - Ford, David A.

AU - Neuschwander-Tetri, Brent A.

AU - Chakraborty, Anutosh

PY - 2021/12

Y1 - 2021/12

N2 - Objective: Obesity and insulin resistance greatly increase the risk of nonalcoholic fatty liver disease and steatohepatitis (NAFLD/NASH). We have previously discovered that whole-body and adipocyte-specific Ip6k1deletion protects mice from high-fat-diet-induced obesity and insulin resistance due to improved adipocyte thermogenesis and insulin signaling. Here, we aimed to determine the impact of hepatocyte-specific and whole-body Ip6k1 deletion (HKO and Ip6k1-KO or KO) on liver metabolism and NAFLD/NASH. Methods: Body weight and composition; energy expenditure; glycemic profiles; and serum and liver metabolic, inflammatory, fibrotic and toxicity parameters were assessed in mice fed Western and high-fructose diet (HFrD) (WD: 40% kcal fat, 1.25% cholesterol, no added choline and HFrD: 60% kcal fructose). Mitochondrial oxidative capacity was evaluated in isolated hepatocytes. RNA-Seq was performed in liver samples. Livers from human NASH patients were analyzed by immunoblotting and mass spectrometry. Results: HKO mice displayed increased hepatocyte mitochondrial oxidative capacity and improved insulin sensitivity but were not resistant to body weight gain. Improved hepatocyte metabolism partially protected HKO mice from NAFLD/NASH. In contrast, enhanced whole-body metabolism and reduced body fat accumulation significantly protected whole-body Ip6k1-KO mice from NAFLD/NASH. Mitochondrial oxidative pathways were upregulated, whereas gluconeogenic and fibrogenic pathways were downregulated in Ip6k1-KO livers. Furthermore, IP6K1 was upregulated in human NASH livers and interacted with the enzyme O-GlcNAcase that reduces protein O-GlcNAcylation. Protein O-GlcNAcylation was found to be reduced in Ip6k1-KO and HKO mouse livers. Conclusion: Pleiotropic actions of IP6K1 in the liver and other metabolic tissues mediate hepatic metabolic dysfunction and NAFLD/NASH, and thus IP6K1 deletion may be a potential treatment target for this disease.

AB - Objective: Obesity and insulin resistance greatly increase the risk of nonalcoholic fatty liver disease and steatohepatitis (NAFLD/NASH). We have previously discovered that whole-body and adipocyte-specific Ip6k1deletion protects mice from high-fat-diet-induced obesity and insulin resistance due to improved adipocyte thermogenesis and insulin signaling. Here, we aimed to determine the impact of hepatocyte-specific and whole-body Ip6k1 deletion (HKO and Ip6k1-KO or KO) on liver metabolism and NAFLD/NASH. Methods: Body weight and composition; energy expenditure; glycemic profiles; and serum and liver metabolic, inflammatory, fibrotic and toxicity parameters were assessed in mice fed Western and high-fructose diet (HFrD) (WD: 40% kcal fat, 1.25% cholesterol, no added choline and HFrD: 60% kcal fructose). Mitochondrial oxidative capacity was evaluated in isolated hepatocytes. RNA-Seq was performed in liver samples. Livers from human NASH patients were analyzed by immunoblotting and mass spectrometry. Results: HKO mice displayed increased hepatocyte mitochondrial oxidative capacity and improved insulin sensitivity but were not resistant to body weight gain. Improved hepatocyte metabolism partially protected HKO mice from NAFLD/NASH. In contrast, enhanced whole-body metabolism and reduced body fat accumulation significantly protected whole-body Ip6k1-KO mice from NAFLD/NASH. Mitochondrial oxidative pathways were upregulated, whereas gluconeogenic and fibrogenic pathways were downregulated in Ip6k1-KO livers. Furthermore, IP6K1 was upregulated in human NASH livers and interacted with the enzyme O-GlcNAcase that reduces protein O-GlcNAcylation. Protein O-GlcNAcylation was found to be reduced in Ip6k1-KO and HKO mouse livers. Conclusion: Pleiotropic actions of IP6K1 in the liver and other metabolic tissues mediate hepatic metabolic dysfunction and NAFLD/NASH, and thus IP6K1 deletion may be a potential treatment target for this disease.

KW - Hyperglycemia

KW - IP6K1

KW - Liver

KW - Metabolism

KW - NAFLD/NASH

KW - O-GlcNAcylation

UR - http://www.scopus.com/inward/record.url?scp=85119347979&partnerID=8YFLogxK

U2 - 10.1016/j.molmet.2021.101364

DO - 10.1016/j.molmet.2021.101364

M3 - Article

C2 - 34757046

AN - SCOPUS:85119347979

SN - 2212-8778

VL - 54

JO - Molecular Metabolism

JF - Molecular Metabolism

M1 - 101364

ER -

Pleiotropic actions of IP6K1 mediate hepatic metabolic dysfunction to promote nonalcoholic fatty liver disease and steatohepatitis

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Keywords

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