Kupffer cells in non-alcoholic fatty liver disease: The emerging view

Abstract

Summary Non-alcoholic fatty liver disease (NAFLD) has become the most common liver disorder of our times. Simple steatosis, a seemingly innocent manifestation of NAFLD, may progress into steatohepatitis and cirrhosis, but this process is not well understood. Since NAFLD is associated with obesity and insulin resistance, mechanisms that link lipid metabolism to inflammation offer insights into the pathogenesis. An important parallel between obesity-related pathology of adipose tissue and liver pertains to the emerging role of macrophages and evidence is growing that Kupffer cells critically contribute to progression of NAFLD. Toll-like receptors, in particular TLR4, represent a major conduit for danger recognition linked to Kupffer cell activation and this process may be perturbed at multiple steps in NAFLD. Steatosis may interfere with sinusoid microcirculation and hepatocellular clearance of microbial and host-derived danger signals, enhancing responsiveness of Kupffer cells. Altered lipid homeostasis in NAFLD may unfavourably affect TLR4 receptor complex assembly and sorting, interfere with signalling flux redistribution, promote amplification loops, and impair negative regulation including alternative activation of Kupffer cells. These events are further promoted by altered adipokine secretion and reactive oxygen species production. Specific targeting of these interactions may provide more effective strategies in the treatment of NAFLD.

Impact of pretransplant body mass index on the clinical outcome after allogeneic hematopoietic SCT

“…In a multivariate analysis, BMI was not a significant risk factor for chronic GVHD. The cumulative incidence of extensive chronic GVHD was 19.9% in the underweight, 23.7% in normal, 24.9% in overweight and 28.4% in obese groups (P = 0.001, Figure 1f). A multivariate analysis showed that obesity was associated with an increased risk of extensive chronic GVHD (HR 1.32, 95%CI 1.01-1.74, P = 0.043, Supplementary Table 1).…”

“…[13][14][15][16] It is well-known that a prominent obesity-induced immune shift in the liver, so-called non-alcoholic steatohepatitis, causes inflammation in the liver, which might contribute to the subsequent increased risk of hepatic acute GVHD. 18,24 Practically, careful monitoring and early institution of high-dose immunosuppression are suggested. As a possible intervention, weight loss by diet and exercise could be a safe option, and has been shown to dose-dependently improve histological disease activity in non-alcoholic steatohepatitis associated with obesity.…”

Obesity accelerates epigenetic aging of human liver

“…However, even in the absence of structural liver disease, and in mild forms (such as early steatosis), the clinically relevant phenomena in these patients are insulin resistance (with its hepatic component very poorly understood) and an increased risk of HCC as the most tangible manifestations of obesity. Aging and cancer are not only intricately linked to each other (30,31) but also to obesity and metabolic syndrome (32). Obesity is an established risk factor for many types of cancers, particularly for HCC, because of its carcinogenic potential and the association with NAFLD (33).…”

“…Although epigenetic aging may help understand carcinogenesis, it may also have practical consequences. NASH is a risk factor for liver cancer even in the absence of cirrhosis (32) and is thus recommended as a high-risk group for screening in the current American Association for the Study of Liver Diseases guidelines (35). Future HCC screening recommendations may be influenced by our findings because BMIinduced increased tissue age (i) is independent of the presence of overt NASH and (ii) is irreversible, at least in the short term.…”

Hepatitis virus and hepatocellular carcinoma in Brazil: a report from the State of Espírito Santo

“…An increased number of NASH-associated HCC has also been observed in more developed countries 26 , and it is possible that some cryptogenic cases may be related to unidentified NASH, instead, as has been hypothesized previously 5,27,28 . Cryptogenic cases accounted for 19.3% of our sample, which is a greater frequency than that reported for the most recent national survey in Brazil.…”