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.

• Authors: 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
• Journal: Molecular metabolism (Mol Metab) Vol. 54 Pg. 101364 (12 2021) ISSN: 2212-8778 [Electronic] Germany
• PMID: 34757046 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Author(s). Published by Elsevier GmbH.. All rights reserved.

Chemical References

• Dietary Sugars
• Ihpk1 protein, mouse
• Phosphotransferases (Phosphate Group Acceptor)
• IP6K1 protein, human

Topics

• Animals
• Choline Deficiency (metabolism)
• Dietary Sugars (adverse effects)
• Fatty Liver (metabolism)
• Hepatocytes (metabolism)
• Humans
• Mice
• Mice, Inbred C57BL
• Non-alcoholic Fatty Liver Disease (metabolism)
• Phosphotransferases (Phosphate Group Acceptor) (deficiency, genetics, metabolism)