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Hepatocyte Lethal and Nonlethal Lipotoxic Injury

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Cellular Injury in Liver Diseases

Part of the book series: Cell Death in Biology and Diseases ((CELLDEATH))

Abstract

Hepatocyte injury caused by accumulation of excess lipid intermediates, known as hepatocyte lipotoxicity, is intricately linked to the pathogenesis of obesity-associated nonalcoholic steatohepatitis (NASH). Although both hepatocyte cell injury and inflammation occur in this disease process, the cellular and molecular mechanisms linking hepatocyte injury to inflammation remain unclear. Although multiple cell types contribute to hepatic inflammation in NASH, the predominant cell types appear to be macrophages. In this review, we discuss lipid-induced apoptosis and sublethal signaling events described in lipid-loaded hepatocytes, and how they promote macrophage-associated inflammation. The saturated free fatty acid palmitate and its derivative lysophosphatidylcholine activate cellular apoptotic pathways by upregulating the proapoptotic proteins, including BH3-only protein PUMA and the death receptor TRAIL-R2, which cooperatively promote lipoapoptosis. Hepatocyte apoptosis may contribute to hepatic inflammation and fibrosis via generation of apoptotic bodies. These apoptotic bodies are engulfed by macrophages and stellate cells promoting liver inflammation and fibrosis, respectively. However, recent studies also suggest that proapoptotic, but nonlethal, signaling in hepatocytes leads to the release of extracellular vesicles, which promote hepatic inflammation by inducing macrophage chemotaxis and activation. The vesicle cargo promoting these macrophage processes includes CXCL10, TRAIL, and sphingosine 1-phosphate. Thus, we discuss the possible relative contributions of both hepatocyte apoptotic cell death and nonlethal proapoptotic signaling in generating macrophage-driven hepatic inflammation during NASH.

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Abbreviations

CAD:

Caspase-activated DNase

CHOP:

CAAT/enhancer binding homologous protein

CXCL10:

Chemokine (C-X-C motif) ligand 10

DAMP:

Damage-associated molecular pattern

ER:

Endoplasmic reticulum

EV:

Extracellular vesicle

IRE1α:

Inositol-requiring enzyme-1α

JNK:

c-Jun N-terminal kinase

LPC:

Lysophosphatidylcholine

MLK3:

Mixed lineage kinase 3

NAFLD:

Nonalcoholic fatty liver disease

NASH:

Nonalcoholic steatohepatitis

ROCK1:

Rho-associated, coiled-coil-containing protein kinase 1

TGFβ:

Transforming growth factor β

TNFR1:

Tumor necrosis factor receptor 1

TRAIL:

Tumor necrosis factor-related apoptosis-inducing ligand

TRAIL-R:

Tumor necrosis factor related apoptosis inducing ligand receptor

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Acknowledgments

This work is supported in part by NIH grants DK41876 (GJG), DK97178 and DK107402 (HM), and KL2TR000136-09 (SHI). Support was also provided to P. Hirsova by the American Liver Foundation and Edward C. Kendall Research Fellowship Award (Mayo Clinic).

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Authors and Affiliations

  1. Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA

    Petra Hirsova, Samar H. Ibrahim, Harmeet Malhi & Gregory J. Gores M.D

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  1. Petra Hirsova
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  2. Samar H. Ibrahim
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  3. Harmeet Malhi
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  4. Gregory J. Gores M.D
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Correspondence to Gregory J. Gores M.D .

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Editors and Affiliations

  1. Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas, USA

    Wen-Xing Ding

  2. Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA

    Xiao-Ming Yin

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Hirsova, P., Ibrahim, S.H., Malhi, H., Gores, G.J. (2017). Hepatocyte Lethal and Nonlethal Lipotoxic Injury. In: Ding, WX., Yin, XM. (eds) Cellular Injury in Liver Diseases. Cell Death in Biology and Diseases. Springer, Cham. https://doi.org/10.1007/978-3-319-53774-0_5

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