Hepatic Crown-Like Structure: A Unique Histological Feature in Non-Alcoholic Steatohepatitis in Mice and Humans

Abstract

Although macrophages are thought to be crucial for the pathogenesis of chronic inflammatory diseases, how they are involved in disease progression from simple steatosis to non-alcoholic steatohepatitis (NASH) is poorly understood. Here we report the unique histological structure termed “hepatic crown-like structures (hCLS)” in the mouse model of human NASH; melanocortin-4 receptor deficient mice fed a Western diet. In hCLS, CD11c-positive macrophages aggregate to surround hepatocytes with large lipid droplets, which is similar to those described in obese adipose tissue. Histological analysis revealed that hCLS is closely associated with activated fibroblasts and collagen deposition. When treatment with clodronate liposomes effectively depletes macrophages scattered in the liver, with those in hCLS intact, hepatic expression of inflammatory and fibrogenic genes is unaffected, suggesting that hCLS is an important source of inflammation and fibrosis during the progression of NASH. Notably, the number of hCLS is positively correlated with the extent of liver fibrosis. We also observed increased number of hCLS in the liver of non-alcoholic fatty liver disease/NASH patients. Collectively, our data provide evidence that hCLS is involved in the development of hepatic inflammation and fibrosis, thereby suggesting its pathophysiologic role in disease progression from simple steatosis to NASH.

Macrophage-inducible C-type lectin underlies obesity-induced adipose tissue fibrosis

“…The data of this study suggest that CLS is an important origin of fibrosis as well as inflammation in adipose tissue. This notion is supported by our recent observations that the CLS-like histological structure in the liver of nonalcoholic steatohepatitis in mice and humans, which may be involved in the fibrogenesis of the liver 26 . Given that Mincle expression is localized to macrophages constituting CLS and that residual lipid droplets of dead adipocytes are scavenged by macrophages within CLS, Mincle can sense as-yet-unidentified endogenous ligands that are released as danger signals from dead adipocytes in the ARTICLE interaction between adipocytes and macrophages.…”

Pathogenesis of Non-alcoholic Steatohepatitis and Its Potential Therapeutic Strategies

“…We found bizarre microstructures in livers from MC4R-KO mice, which are very similar to CLS in obese adipose tissue [ 7 ]. We have called them "hepatic crown-like structures" (hCLS), where macrophages aggregate to surround hepatocytes with large lipid droplets.…”

“…In the NASH liver, macrophages can interact with and engulf dead hepatocytes within hCLS, thereby activating fi brogenic cells to stimulate hepatic fi brosis as an adaptive repair response to tissue injury. It is, therefore, likely that hCLS serves as an origin of hepatic infl ammation and fi brosis during the progression from simple steatosis to NASH [ 7 ].…”

“…Although there was no signifi cant difference in F4/80-positive macrophages between the genotypes, the number of CLS was signifi cantly reduced in Mincle-KO mice. Since the number of hCLS is more positively correlated with the extent of liver fi brosis than that of macrophages in MC4R-KO mice [ 7 ], we examined adipose tissue fi brosis by Masson trichrome staining. There was extensive interstitial fi brosis in the epididymal fat depot from wild-type mice, which was markedly attenuated in Mincle-KO mice together with a signifi cant reduction of collagen deposition.…”

Crown-like Structures in Breast Adipose Tissue from Normal Weight Women: Important Impact

“…Interestingly, it has recently been reported that breast WAT from Black women, who have worse prognosis with breast cancer, have higher density of CLS-B than their non-Black counterparts (22). The probability that WAT inflammation helps to explain the obesity-inflammation-carcinogenesis axis is further supported by observations showing the occurrence of CLS in adipose tissue associated with other malignancies, including oral squamous cell carcinoma of the tongue (23), endometrial cancer (24), and in the report of liver macrophages, identified as Kupffer cells, forming CLS with lipidladen hepatocytes in NAFLD, a disorder now considered to be a precursor for hepatocellular cancer (14,25).…”