Hepatic inflammation is a key pathological feature of Nonalcoholic Steatohepatitis (NASH). Natural Killer T-cells (NKT) and CD8+ T-cells are known to play an important role in obesity related adipose tissue inflammation. We hypothesized that these same inflammatory phenotypes would be present in progressive NASH. We used a previously established high fat high carbohydrate (HFHC) murine obesogenic diet model of progressive NASH to investigate the role of NKT cells and CD8+ T-cells in C57Bl6/J mice. Further, to better understand the impact of these cell populations; CD1d-deficient and CD8+ T-cell depleted mice were subjected to HFHC diet for 16 weeks. C57Bl6/J mice fed HFHC diet had increased body weight, liver triglyceride content, serum alanine aminotransferase (ALT) levels and increased NKT cells and CD8+ T-cells infiltration in the liver. In addition human liver sections from patients with NASH showed increased CD8+ T-cells. In comparison, CD1d-deficient and CD8-T cell depleted mice fed HFHC had lower hepatic triglyceride content, lower ALT levels, as well reduced α-smooth muscle actin (αSMA), collagen type 1 alpha 1 (Col1a1), collagen type 1 alpha 2 (Col1a2) mRNA expression, lower activated resident macrophages and infiltrating macrophages and improved NAFLD activity scores. Further, while CD1d-deficient mice were protected against weight gain on the HFHC diet, CD8 T-cell depleted mice gained weight on the HFHC diet.
Conclusion
We found that NASH has an immunological signature that includes hepatic infiltrating NKT and CD8+ T-Cells. Depletion of these cells resulted in reduced NASH progression and thus presents novel therapeutic avenues for the treatment of NASH.
This is the author manuscript accepted for publication and has undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as
Background and Aims
The augmenter of liver regeneration (ALR) protein is critical for lipid homeostasis and mitochondrial function. We investigated high‐fat/high‐carbohydrate (HF/HC) diet–induced nonalcoholic fatty liver disease (NAFLD) in wild‐type (WT), hepatocyte‐specific ALR‐knockout (ALR‐H‐KO), and ALR‐heterozygous (ALR‐H‐HET) mice. ALR was measured in serum of human nonalcoholic steatohepatitis (NASH) and NASH‐induced cirrhosis (serum and liver).
Approach and Results
HF/HC feeding decreased ALR expression in all groups of mice. The otherwise normal ALR‐H‐HET mice gained more weight and steatosis than WT mice when challenged metabolically with the HF/HC diet; ALR‐H‐KO mice gained the least weight and had the least steatosis. These findings were consistent with correspondingly increased triglycerides and cholesterol and altered expression of carnitine palmitoyltransferase 1a, sterol regulatory element‐binding protein, acetyl coenzyme A carboxylase, and fatty acid synthase. All HF/HC‐fed mice developed insulin resistance, the magnitude being lower in ALR‐H‐KO mice. HF/HC‐fed ALR‐H‐HET mice were more resistant to glucose challenge than WT or ALR‐H‐KO mice. The frequency of tumor necrosis factor alpha–producing, interleukin 6 (IL6)–producing, and IL17‐producing cells was greater in ALR‐H‐KO than ALR‐H‐HET and lowest in WT mice. HF/HC feeding did not increase their number in ALR‐H‐KO mice, and the increase in ALR‐H‐HET was greater than that in WT mice except for IL17 cells. Cluster of differentiation 25–positive (CD25+) forkhead box P3–positive CD4+ regulatory T‐cell frequency was lower in ALR‐H‐HET than WT mice and further reduced in ALR‐H‐KO mice; HF/HC reduced regulatory T‐cell frequency only in WT mice. HF/HC‐fed ALR‐H‐HET, but not WT, mice developed fibrosis; and ALR‐H‐KO mice progressed to cirrhosis. White adipose tissue of HF/HC‐fed ALR‐deficient mice developed strong inflammation, indicating bidirectional interactions with the liver. Hepatic and serum ALR levels were significantly reduced in patients with NASH‐cirrhosis. Serum ALR was also significantly lower in patients with NASH.
Conclusions
Hepatic ALR deficiency may be a critical predisposing factor for aggressive NAFLD progression.
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Although pediatric liver transplantation (LT) results in excellent long-term outcomes, a high incidence of early acute cellular rejection and late graft fibrosis persists. Routine measurement of allograft enzymes may not reliably detect rejection episodes, identify candidates for immunosuppression minimization, or indicate allograft fibrosis. Surveillance biopsies (SBs) can provide valuable information in this regard, but their role in pediatric LT is not fully established. A retrospective cohort of 236 pediatric LT recipients from a high-volume center was studied to characterize the risks and benefits of SB versus for-cause biopsies (FCBs). The study population was 47.1% male and 54.7% Hispanic, and 31% received living donor grafts. Our data suggest that patients in the SB group had better transplant outcomes (rejection-free, graft, and patient survival) compared with patients who had FCBs or who never underwent biopsy. Among 817 biopsies obtained from 236 patients, 150 (18.4%) were SBs. Only 6 patients had a biopsy-related complication, and none were observed in the SB subset. Graft biochemical blood tests did not accurately predict rejection severity on biopsy, with aspartate aminotransferase area under the receiver operating characteristic curve (AUROC) 0.66, alanine aminotransferase AUROC 0.65 (very poor predictions), and gammaglutamyltransferase AUROC 0.58 (no prediction). SBs identified subclinical rejection in 18.6% of biopsies, whereas 63.3% of SBs had evidence of fibrosis. SBs prompted changes in immunosuppression including dose reduction. Our experience suggests that SB in pediatric LT is safe, offers valuable information about subclinical rejection episodes, and can guide management of immunosuppression, including minimization. Improved outcomes with SB were likely multifactorial, potentially relating to a more favorable early posttransplant course and possible effect of management optimization through SB. Further multicenter studies are needed to examine the role of SBs on long-term outcomes in pediatric LT.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.