Carbon Tetrachloride Does Not Promote Hepatic Fibrosis in Ob/ob Mice Via Downregulation of Lipocalin-2 Protein

Overview

Journal Redox Biol

Date 2025 Jan 20

PMID 39832399

Authors

Hyun Joo Shin

Kyung Eun Kim

Hyeong Seok An

Eun Ae Jeong

Jiwon Oh

Yundong Sun

Dong-Ju Park

Jaewoong Lee

Jinsung Yang

Gu Seob Roh

Affiliations

Soon will be listed here.

Abstract

Although leptin-deficient ob/ob mice have been investigated to determine whether hepatic steatosis promotes susceptibility to hepatotoxic insults, carbon tetrachloride (CCl)-induced hepatic fibrosis in ob/ob mice remains largely unknown. In this study, we evaluate the pathogenic mechanisms of hepatic fibrosis in CCl-treated wild-type (WT) and ob/ob mice and analyze some parameters related to lipogenesis, inflammation, fibrosis, oxidative stress, apoptosis, and autophagy. CCl treatment attenuated liver weight and lipogenesis in ob/ob mice. Increased hepatic fibrosis-related proteins were reduced in CCl-treated ob/ob mice compared with CCl-treated WT mice. Specifically, the expression of lipocalin-2 (LCN2) was markedly reduced in CCl-treated ob/ob mice versus CCl-treated WT mice. Compared with CCl-treated WT mice, CCl-treated ob/ob mice had reduced expression of neutrophil-related inflammatory genes and proteins. Hepatic heme oxygenase-1 protein was reduced in CCl-treated ob/ob mice compared with CCl-treated WT mice. However, CCl did not promote hepatic apoptosis in ob/ob mice. Therefore, these findings highlight LCN2 as a key signaling factor in CCl-induced hepatic fibrosis.

References

Walton P, Brees C, Lismont C, Apanasets O, Fransen M . The peroxisomal import receptor PEX5 functions as a stress sensor, retaining catalase in the cytosol in times of oxidative stress. Biochim Biophys Acta Mol Cell Res. 2017; 1864(10):1833-1843. DOI: 10.1016/j.bbamcr.2017.07.013. View

Stejskal D, Karpisek M, Humenanska V, Hanulova Z, Stejskal P, Kusnierova P . Lipocalin-2: development, analytical characterization, and clinical testing of a new ELISA. Horm Metab Res. 2008; 40(6):381-5. DOI: 10.1055/s-2008-1062746. View

Ikejima K, Honda H, Yoshikawa M, Hirose M, Kitamura T, Takei Y . Leptin augments inflammatory and profibrogenic responses in the murine liver induced by hepatotoxic chemicals. Hepatology. 2001; 34(2):288-97. DOI: 10.1053/jhep.2001.26518. View

Asimakopoulou A, Weiskirchen S, Weiskirchen R . Lipocalin 2 (LCN2) Expression in Hepatic Malfunction and Therapy. Front Physiol. 2016; 7:430. PMC: 5037186. DOI: 10.3389/fphys.2016.00430. View

Malaguarnera L, Madeddu R, Palio E, Arena N, Malaguarnera M . Heme oxygenase-1 levels and oxidative stress-related parameters in non-alcoholic fatty liver disease patients. J Hepatol. 2005; 42(4):585-91. DOI: 10.1016/j.jhep.2004.11.040. View

Heeboll S, Poulsen M, Ornstrup M, Kjaer T, Pedersen S, Nielsen S . Circulating sCD36 levels in patients with non-alcoholic fatty liver disease and controls. Int J Obes (Lond). 2016; 41(2):262-267. DOI: 10.1038/ijo.2016.223. View

Tan Y, Huang Y, Mei R, Mao F, Yang D, Liu J . HucMSC-derived exosomes delivered BECN1 induces ferroptosis of hepatic stellate cells via regulating the xCT/GPX4 axis. Cell Death Dis. 2022; 13(4):319. PMC: 8993870. DOI: 10.1038/s41419-022-04764-2. View

Leclercq I, Field J, Farrell G . Leptin-specific mechanisms for impaired liver regeneration in ob/ob mice after toxic injury. Gastroenterology. 2003; 124(5):1451-64. DOI: 10.1016/s0016-5085(03)00270-1. View

Zeng H, Qin H, Liao M, Zheng E, Luo X, Xiao A . CD36 promotes de novo lipogenesis in hepatocytes through INSIG2-dependent SREBP1 processing. Mol Metab. 2022; 57:101428. PMC: 8810570. DOI: 10.1016/j.molmet.2021.101428. View

10.

Krishnan A, Li X, Kao W, Viker K, Butters K, Masuoka H . Lumican, an extracellular matrix proteoglycan, is a novel requisite for hepatic fibrosis. Lab Invest. 2012; 92(12):1712-25. PMC: 3810270. DOI: 10.1038/labinvest.2012.121. View

11.

Diehl A . Lessons from animal models of NASH. Hepatol Res. 2005; 33(2):138-44. DOI: 10.1016/j.hepres.2005.09.022. View

12.

Picard C, Lambotte L, Starkel P, Sempoux C, Saliez A, Van Den Berge V . Steatosis is not sufficient to cause an impaired regenerative response after partial hepatectomy in rats. J Hepatol. 2002; 36(5):645-52. DOI: 10.1016/s0168-8278(02)00038-7. View

13.

Han C, Liu Y, Dai R, Ismail N, Su W, Li B . Ferroptosis and Its Potential Role in Human Diseases. Front Pharmacol. 2020; 11:239. PMC: 7090218. DOI: 10.3389/fphar.2020.00239. View

14.

Choi Y, Kim Y . Beneficial and Detrimental Roles of Heme Oxygenase-1 in the Neurovascular System. Int J Mol Sci. 2022; 23(13). PMC: 9266949. DOI: 10.3390/ijms23137041. View

15.

Brix A, Elgavish A, Nagy T, Gower B, Rhead W, Wood P . Evaluation of liver fatty acid oxidation in the leptin-deficient obese mouse. Mol Genet Metab. 2002; 75(3):219-26. DOI: 10.1006/mgme.2002.3298. View

16.

Fan X, Lin L, Cui B, Zhao T, Mao L, Song Y . Therapeutic potential of genipin in various acute liver injury, fulminant hepatitis, NAFLD and other non-cancer liver diseases: More friend than foe. Pharmacol Res. 2020; 159:104945. DOI: 10.1016/j.phrs.2020.104945. View

17.

Raffaele M, Carota G, Sferrazzo G, Licari M, Barbagallo I, Sorrenti V . Inhibition of Heme Oxygenase Antioxidant Activity Exacerbates Hepatic Steatosis and Fibrosis . Antioxidants (Basel). 2019; 8(8). PMC: 6719023. DOI: 10.3390/antiox8080277. View

18.

Koteish A, Diehl A . Animal models of steatohepatitis. Best Pract Res Clin Gastroenterol. 2002; 16(5):679-90. DOI: 10.1053/bega.2002.0332. View

19.

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

20.

Kleiner D, Brunt E, Van Natta M, Behling C, Contos M, Cummings O . Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005; 41(6):1313-21. DOI: 10.1002/hep.20701. View