Pleiotropic Actions of IP6K1 Mediate Hepatic Metabolic Dysfunction to Promote Nonalcoholic Fatty Liver Disease and Steatohepatitis

Overview

Journal Mol Metab

Specialty Cell Biology

Date 2021 Nov 10

PMID 34757046

Citations 8

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

Affiliations

Soon will be listed here.

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.

Citing Articles

Inositol Phosphates and Synthesizing Enzymes: Implications in Neurodegenerative Disorders.

Onu C, Adu M, Chakkour M, Kumar V, Greenberg M Biomolecules. 2025; 15(2).

PMID: 40001529 PMC: 11853280. DOI: 10.3390/biom15020225.

Insights into the roles of inositol hexakisphosphate kinase 1 (IP6K1) in mammalian cellular processes.

Chakkour M, Greenberg M J Biol Chem. 2024; 300(4):107116.

PMID: 38403246 PMC: 11065760. DOI: 10.1016/j.jbc.2024.107116.

Shaping the Future of Obesity Treatment: In Silico Multi-Modeling of IP6K1 Inhibitors for Obesity and Metabolic Dysfunction.

Mondal I, Halder A, Pattanayak N, Mandal S, Cordeiro M Pharmaceuticals (Basel). 2024; 17(2).

PMID: 38399478 PMC: 10891520. DOI: 10.3390/ph17020263.

Depleting inositol pyrophosphate 5-InsP7 protected the heart against ischaemia-reperfusion injury by elevating plasma adiponectin.

Fu L, Du J, Furkert D, Shipton M, Liu X, Aguirre T Cardiovasc Res. 2024; 120(8):954-970.

PMID: 38252884 PMC: 11218692. DOI: 10.1093/cvr/cvae017.

Functions, Mechanisms, and therapeutic applications of the inositol pyrophosphates 5PP-InsP and InsP in mammalian cells.

Qi J, Shi L, Zhu L, Chen Y, Zhu H, Cheng W J Cardiovasc Transl Res. 2023; 17(1):197-215.

PMID: 37615888 DOI: 10.1007/s12265-023-10427-0.

References

Zhang K, Yin R, Yang X . O-GlcNAc: A Bittersweet Switch in Liver. Front Endocrinol (Lausanne). 2015; 5:221. PMC: 4269194. DOI: 10.3389/fendo.2014.00221. View

Jensen T, Abdelmalek M, Sullivan S, Nadeau K, Green M, Roncal C . Fructose and sugar: A major mediator of non-alcoholic fatty liver disease. J Hepatol. 2018; 68(5):1063-1075. PMC: 5893377. DOI: 10.1016/j.jhep.2018.01.019. View

Baffy G, Zhang C, Glickman J, Lowell B . Obesity-related fatty liver is unchanged in mice deficient for mitochondrial uncoupling protein 2. Hepatology. 2002; 35(4):753-61. DOI: 10.1053/jhep.2002.32028. View

Lee S, Nam M, Lee D, Park J, Kang B, Lee D . Silibinin Ameliorates -GlcNAcylation and Inflammation in a Mouse Model of Nonalcoholic Steatohepatitis. Int J Mol Sci. 2018; 19(8). PMC: 6121629. DOI: 10.3390/ijms19082165. View

Chatham J, Zhang J, Wende A . Role of -Linked -Acetylglucosamine Protein Modification in Cellular (Patho)Physiology. Physiol Rev. 2020; 101(2):427-493. PMC: 8428922. DOI: 10.1152/physrev.00043.2019. View

Neuschwander-Tetri B . Therapeutic Landscape for NAFLD in 2020. Gastroenterology. 2020; 158(7):1984-1998.e3. DOI: 10.1053/j.gastro.2020.01.051. View

Illies C, Gromada J, Fiume R, Leibiger B, Yu J, Juhl K . Requirement of inositol pyrophosphates for full exocytotic capacity in pancreatic beta cells. Science. 2007; 318(5854):1299-302. DOI: 10.1126/science.1146824. View

Kim M, Krawczyk S, Doridot L, Fowler A, Wang J, Trauger S . ChREBP regulates fructose-induced glucose production independently of insulin signaling. J Clin Invest. 2016; 126(11):4372-4386. PMC: 5096918. DOI: 10.1172/JCI81993. View

Zhang B, Li M, Yin R, Liu Y, Yang Y, Mitchell-Richards K . O-GlcNAc transferase suppresses necroptosis and liver fibrosis. JCI Insight. 2019; 4(21). PMC: 6948774. DOI: 10.1172/jci.insight.127709. View

10.

Szijgyarto Z, Garedew A, Azevedo C, Saiardi A . Influence of inositol pyrophosphates on cellular energy dynamics. Science. 2011; 334(6057):802-5. DOI: 10.1126/science.1211908. View

11.

Hou Q, Liu F, Chakraborty A, Jia Y, Prasad A, Yu H . Inhibition of IP6K1 suppresses neutrophil-mediated pulmonary damage in bacterial pneumonia. Sci Transl Med. 2018; 10(435). PMC: 6435359. DOI: 10.1126/scitranslmed.aal4045. View

12.

Puhl-Rubio A, Stashko M, Wang H, Hardy P, Tyagi V, Li B . Use of Protein Kinase-Focused Compound Libraries for the Discovery of New Inositol Phosphate Kinase Inhibitors. SLAS Discov. 2018; 23(9):982-988. PMC: 6148399. DOI: 10.1177/2472555218775323. View

13.

Liao G, Ye W, Heitmann T, Ernst G, DePasquale M, Xu L . Identification of Small-Molecule Inhibitors of Human Inositol Hexakisphosphate Kinases by High-Throughput Screening. ACS Pharmacol Transl Sci. 2021; 4(2):780-789. PMC: 8033760. DOI: 10.1021/acsptsci.0c00218. View

14.

Moritoh Y, Oka M, Yasuhara Y, Hozumi H, Iwachidow K, Fuse H . Inositol Hexakisphosphate Kinase 3 Regulates Metabolism and Lifespan in Mice. Sci Rep. 2016; 6:32072. PMC: 5006000. DOI: 10.1038/srep32072. View

15.

Loomba R, Friedman S, Shulman G . Mechanisms and disease consequences of nonalcoholic fatty liver disease. Cell. 2021; 184(10):2537-2564. DOI: 10.1016/j.cell.2021.04.015. View

16.

McCommis K, Chen Z, Fu X, McDonald W, Colca J, Kletzien R . Loss of Mitochondrial Pyruvate Carrier 2 in the Liver Leads to Defects in Gluconeogenesis and Compensation via Pyruvate-Alanine Cycling. Cell Metab. 2015; 22(4):682-94. PMC: 4598280. DOI: 10.1016/j.cmet.2015.07.028. View

17.

Zhu Q, Ghoshal S, Rodrigues A, Gao S, Asterian A, Kamenecka T . Adipocyte-specific deletion of Ip6k1 reduces diet-induced obesity by enhancing AMPK-mediated thermogenesis. J Clin Invest. 2016; 126(11):4273-4288. PMC: 5096898. DOI: 10.1172/JCI85510. View

18.

Chakraborty A . The inositol pyrophosphate pathway in health and diseases. Biol Rev Camb Philos Soc. 2017; 93(2):1203-1227. PMC: 6383672. DOI: 10.1111/brv.12392. View

19.

Ioannou G . The Role of Cholesterol in the Pathogenesis of NASH. Trends Endocrinol Metab. 2015; 27(2):84-95. DOI: 10.1016/j.tem.2015.11.008. View

20.

Thomas M, Potter B . The enzymes of human diphosphoinositol polyphosphate metabolism. FEBS J. 2013; 281(1):14-33. PMC: 4063336. DOI: 10.1111/febs.12575. View