Macrophage-derived thrombospondin 1 promotes obesity-associated non-alcoholic fatty liver disease

Autor: Taesik Gwag, Shuxia Wang, Eun Y. Lee, Dong Li, Raja Gopal Reddy Mooli, Sangderk Lee
Rok vydání: 2021
Předmět:
HFD
high-fat diet
Cirrhosis
Th
T helper type
Macrophage
AST
aspartate aminotransferase
Chronic liver disease
α-SMA
smooth muscle actin
TNF
tumour necrosis factor
TSP1
TSP1
thrombospondin 1
DEG
differentially expressed gene
IL-
interleukin
Immunology and Allergy
Medicine
TGF
transforming growth factor
scRNA-seq
single-cell RNA sequencing
Liver injury
NAS
NAFLD activity score
Fatty liver
NASH
SMPDL3B
Gastroenterology
AMLN
amylin liver NASH
ASMase
acid sphingomyelinase
BMDM
bone marrow-derived macrophage
HSC
hepatic stellate cell
ECM
extracellular matrix
SMPDL3B
sphingomyelin phosphodiesterase acid-like 3B
LPS
lipopolysaccharide
Research Article
TLR
Toll-like receptor
GPI
glycosylphosphatidylinositol
NAFLD
non-alcoholic fatty liver disease
NASH
non-alcoholic steatohepatitis
NF-κB
nuclear factor-κB
KEGG
Kyoto Encyclopedia of Genes and Genomes
MP
mononuclear phagocyte
digestive system
Tsp1Δmɸ
macrophage-specific TSP1-knockout mice
Insulin resistance
NAFLD
ALT
alanine aminotransferase
Internal Medicine
KC
Kupffer cell
Tsp1Δadipo
adipocyte-specific TSP1-knockout mice
Obesity
lcsh:RC799-869
Hepatology
EC
endothelial cell
business.industry
nutritional and metabolic diseases
medicine.disease
digestive system diseases
LFD
low-fat diet
SREBP1c
sterol regulatory element-binding protein-1 c
Cancer research
Hepatic stellate cell
Tsp1fl/fl
TSP1 floxed mice
lcsh:Diseases of the digestive system. Gastroenterology
MDM
monocyte-derived macrophage
qPCR
quantitative PCR
Steatosis
Steatohepatitis
business
Zdroj: JHEP Reports
JHEP Reports, Vol 3, Iss 1, Pp 100193-(2021)
ISSN: 2589-5559
DOI: 10.1016/j.jhepr.2020.100193
Popis: Background & Aims Thrombospondin 1 (TSP1) is a multifunctional matricellular protein. We previously showed that TSP1 has an important role in obesity-associated metabolic complications, including inflammation, insulin resistance, cardiovascular, and renal disease. However, its contribution to obesity-associated non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD or NASH) remains largely unknown; thus, we aimed to determine its role. Methods High-fat diet or AMLN (amylin liver NASH) diet-induced obese and insulin-resistant NAFLD/NASH mouse models were utilised, in addition to tissue-specific Tsp1-knockout mice, to determine the contribution of different cellular sources of obesity-induced TSP1 to NAFLD/NASH development. Results Liver TSP1 levels were increased in experimental obese and insulin-resistant NAFLD/NASH mouse models as well as in obese patients with NASH. Moreover, TSP1 deletion in adipocytes did not protect mice from diet-induced NAFLD/NASH. However, myeloid/macrophage-specific TSP1 deletion protected mice against obesity-associated liver injury, accompanied by reduced liver inflammation and fibrosis. Importantly, this protection was independent of the levels of obesity and hepatic steatosis. Mechanistically, through an autocrine effect, macrophage-derived TSP1 suppressed Smpdl3b expression in liver, which amplified liver proinflammatory signalling (Toll-like receptor 4 signal pathway) and promoted NAFLD progression. Conclusions Macrophage-derived TSP1 is a significant contributor to obesity-associated NAFLD/NASH development and progression and could serve as a therapeutic target for this disease. Lay summary Obesity-associated non-alcoholic fatty liver disease is a most common chronic liver disease in the Western world and can progress to liver cirrhosis and cancer. No treatment is currently available for this disease. The present study reveals an important factor (macrophage-derived TSP1) that drives macrophage activation and non-alcoholic fatty liver disease development and progression and that could serve as a therapeutic target for non-alcoholic fatty liver disease/steatohepatitis.
Graphical abstract
Highlights • Obesity induces TSP1 expression in several tissues, such as adipose tissue and liver. • Macrophages are an important cellular source of increased TSP1 in mouse NASH livers. • Deletion of TSP1 in macrophages protects mice from diet-induced NASH. • SMPDL3B negatively regulates TSP1-mediated macrophage activation.
Databáze: OpenAIRE
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