Thesis

eIF2α-ATF4 Signaling Mediates NASH Progression through Suppression of Kupffer Cells Polarization toward The M2 Subtype”

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Nonalcoholic steatohepatitis (NASH) is a complex liver condition marked by hepatic steatosis, injury,
inflammation, and fibrosis. It is often triggered by obesity-induced ER stress which activates the
integrated stress response (ISR) pathway. This pathway, involving eIF2α and ATF4, contributes to NASH
progression, particularly fibrosis via hepatic stellate cells (HSCs) activation. However, its impact on NASH
inflammation, regulated by Kupffer cell polarization, remains largely unexplored. Recent research
suggests that eIF2α/ATF4 signaling may exacerbate inflammation by suppressing M2 macrophage
polarization, offering new insights into NASH pathogenesis. Thus, this study aims to investigate the role
of ISR in NASH progression in mice fed a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD),
focusing on M1 and M2 Kupffer cell (KC) subtypes. In-vivo studies involving myeloid-specific
ATF4-deficient mice and administering ISR inhibitor (ISRIB) alongside CDAHFD were performed. Several
experiments including qPCR, western blot, and histology analysis were conducted to measure NASH
progression. eIF2α-ATF4 signaling mediates NASH progression by suppressing Kupffer cell polarization
towards the M2 subtype. The eIF2α/ATF4 signaling pathway was activated during NASH progression.
Blocking the eIF2α/ATF4 pathway with ISRIB significantly reduced liver inflammation and fibrosis,
improving NASH outcomes. Myeloid-specific ATF4 deficiency protected the liver against NASH, reducing
inflammation, fibrosis, steatosis, and ballooning, highlighting the macrophage eIF2α/ATF4 pathway's role
in chronic inflammation. ISRIB administration restored the M1/M2 macrophage balance during NASH
progression. These findings suggest ISRIB is a promising therapeutic strategy for NAFLD, particularly
NASH.

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Availability

Detail Information

Series Title

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Call Number

BM 24-015

Publisher

i3L, Jakarta : i3L Press., 2024

Collation

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Language

English

ISBN/ISSN

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Classification

NONE

Content Type

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Media Type

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Carrier Type

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Edition

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Subject(s)

NASH
ISR
eIF2α/ATF4 signaling pathway
Kupffer cells
ISRIB

Specific Detail Info

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Statement of Responsibility

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