Highlights
- •CCL3 levels were elevated in both serum and liver of NASH patients and animal model of NASH.
- •CCL3 protein colocalized with liver macrophages, especially proinflammatory M1-like macrophages.
- •Deficient in CCL3 attenuated liver macrophage recruitment and promoted M2 macrophage polarization, resulting in prevented diet-induced steatohepatitis, hepatic fibrosis, and insulin resistance.
- •CCL3 deletion in bone marrow cells and ob/ob mice prevented diet-induced steatohepatitis, hepatic fibrosis, and insulin resistance.
Abstract
Background and aims
The global prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing. Chemokines
and their receptors have potential as therapeutic targets of NAFLD. We investigated
the role of C C chemokine ligand 3 (CCL3) in the development of murine and human NAFLD.
Methods
CCL3-knockout mice (CCL3−/−) and littermate CCL3 wild-type control mice (WT) were fed a high-cholesterol and
high-fat (CL) diet for 16 weeks to induce NAFLD. We investigated the impact of CCL3
gene deletion in bone marrow cells and leptin-deficient ob/ob mice on CL diet-induced steatohepatitis. We assayed the serum CCL3 levels in 36 patients
with biopsy-proven NAFLD and nine healthy control subjects.
Results
Compared with normal chow (NC), the CL diet induced steatohepatitis and hepatic fibrosis
and elevated the plasma CCL3 level. In the liver, CCL3 protein colocalized with F4/80+ macrophages, especially CD11c+ M1-like macrophages, rather than other cell types. CCL3−/− attenuated CL diet-induced steatohepatitis and fibrosis associated with M2-dominant
liver macrophages compared with the WT. The reconstitution of bone marrow (BM) cells
from CCL3−/− attenuated steatohepatitis in WT mice fed a CL diet. Furthermore, crossing CCL3−/− onto the ob/ob background prevented CL diet-induced NAFLD in ob/ob mice, which was associated with a lesser inflammatory phenotype of liver macrophages.
Also, the serum and hepatic levels of CCL3 were significantly increased in patients
with non-alcoholic steatohepatitis (NASH) compared to those with simple fatty liver
(NAFL) and healthy subjects.
Conclusion
Our data indicate that CCL3 facilitates macrophage infiltration into the liver and
M1 polarization in the progression of steatohepatitis and highlight the need for further
studies to determine the effect of CCL3-CCR1 and -CCR5 signaling blockade on the treatment
of NAFLD.
Abbreviations:
Acox (acyl-coenzyme A oxidase), ALT (alanine aminotransferase), Arg (arginine), AST (aspartate aminotransferase), BM (bone marrow), CCL (CC chemokine ligand), CCR (CC chemokine receptor), CL (high-cholesterol and high-fat diet), Col1α1 (collagen type I alpha 1), Cpt (carnitine palmitoyltransferase), DMEM (Dulbecco's modified Eagle's medium), FBS (fetal bovine serum), ER (endoplasmic reticulum), ERK (extracellular signal-regulated protein kinase), Fas (fatty acid synthase), GTT (glucose tolerance test), HSC (hepatic stellate cell), IL (interleukin), JNK (c-Jun N-terminal protein kinase), Lcad (long-chain acyl-CoA dehydrogenase), LPS (lipopolysaccharide), MAPK (mitogen-activated protein kinase), NAFLD (non-alcoholic fatty liver disease), NASH (non-alcoholic steatohepatitis), NC (normal chow), NEFA (non-esterified fatty acids), Pai-1 (plasminogen activator inhibitor-1), PCR (polymerase chain reaction), Pgc (peroxisome proliferative activated receptor-gamma coactivator), Ppar (peroxisome proliferator activated receptor), PTT (pyruvate tolerance test), ROS (reactive oxygen species), SMA (smooth muscle actin), Srebp (sterol regulatory element-binding protein), TBARS (thiobarbituric acid reactive substances), TC (total cholesterol), Tgf (transforming growth factor), TG (triglyceride), Tnf (tumor necrosis factor), WT (wild type)Keywords
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Article info
Publication history
Published online: October 14, 2021
Accepted:
October 12,
2021
Received:
July 14,
2021
Identification
Copyright
© 2021 Elsevier Inc. All rights reserved.
