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Imaging and immunometabolic phenotyping uncover changes in the hepatic immune response in the early phases of NAFLD
- Source :
- JHEP Reports, Vol 2, Iss 4, Pp 100117-(2020), JHEP Reports
- Publication Year :
- 2020
- Publisher :
- Elsevier BV, 2020.
-
Abstract
- Background & Aims The precise determination of non-alcoholic fatty liver disease (NAFLD) onset is challenging. Thus, the initial hepatic responses to fat accumulation, which may be fundamental to our understanding of NAFLD evolution and clinical outcomes, are largely unknown. Herein, we chronologically mapped the immunologic and metabolic changes in the liver during the early stages of fatty liver disease in mice and compared this with human NAFLD samples. Methods Liver biopsies from patients with NAFLD (NAFLD activity score [NAS] 2–3) were collected for gene expression profiling. Mice received a high-fat diet for short periods to mimic initial steatosis and the hepatic immune response was investigated using a combination of confocal intravital imaging, gene expression, cell isolation, flow cytometry and bone marrow transplantation assays. Results We observed major immunologic changes in patients with NAS 2–3 and in mice in the initial stages of NAFLD. In mice, these changes significantly increased mortality rates upon drug-induced liver injury, as well as predisposing mice to bacterial infections. Moreover, deletion of Toll-like receptor 4 in liver cells dampened tolerogenesis, particularly in Kupffer cells, in the initial stages of dietary insult. Conclusion The hepatic immune system acts as a sentinel for early and minor changes in hepatic lipid content, mounting a biphasic response upon dietary insult. Priming of liver immune cells by gut-derived Toll-like receptor 4 ligands plays an important role in liver tolerance in initial phases, but continuous exposure to insults may lead to damage and reduced ability to control infections. Lay summary Fatty liver is a very common form of hepatic disease, leading to millions of cases of cirrhosis every year. Patients are often asymptomatic until becoming very sick. Therefore, it is important that we expand our knowledge of the early stages of disease pathogenesis, to enable early diagnosis. Herein, we show that even in the early stages of fatty liver disease, there are significant alterations in genes involved in the inflammatory response, suggesting that the hepatic immune system is disturbed even following minor and undetectable changes in liver fat content. This could have implications for the diagnosis and clinical management of fatty liver disease.<br />Graphical abstract<br />Highlights • Hepatic immune response is already altered in liver biopsies from patients with mild NAFLD. • We designed a novel mouse model to mimic mild NAFLD, enabling the chronological mapping of liver changes. • This revealed an increased mortality rate upon secondary liver damage and a window of increased susceptibility to infection. • NAFLD diagnosis may be significantly improved by a more profound investigation of changes in hepatic immunology. • These data could guide customized nutritional and therapeutic interventions at different stages of NAFLD.
- Subjects :
- HFD, high-fat diet
Cirrhosis
PROGRESSION
DISEASE
steatosis
Immunology and Allergy
NONALCOHOLIC FATTY LIVER
METABOLIC SYNDROME
Liver injury
NAS, NAFLD activity score
in vivo imaging
Fatty liver
Gastroenterology
CFUs, colony forming units
DCs, dendritic cells
Life Sciences & Biomedicine
Research Article
NAFLD, non-alcoholic fatty liver disease
SD, standard diet
APAP, acetaminophen
liver
Immune system
INFLAMMATION
Immunity
ALT, alanine aminotransferase
NAFLD
INJURY
Internal Medicine
medicine
lcsh:RC799-869
ITT, insulin tolerance test
NPCs, non-parenchymal cells
Science & Technology
Gastroenterology & Hepatology
RECEPTOR
Hepatology
business.industry
TLR4, Toll-like receptor 4
medicine.disease
WT, wild-type
immunity
DYSFUNCTION
Hepatic immune response
immune system
CELLS
Immunology
TLR4
KCs, Kupffer cells
lcsh:Diseases of the digestive system. Gastroenterology
E. coli, Escherichia coli
Steatosis
diet
business
metabolism
Subjects
Details
- ISSN :
- 25895559
- Volume :
- 2
- Database :
- OpenAIRE
- Journal :
- JHEP Reports
- Accession number :
- edsair.doi.dedup.....3713a751be0ec2e38f6af369ad3195f2