Association between endotoxemia and histological features of nonalcoholic fatty liver disease

Abstract

AIMTo assess whether surrogate biomarkers of endotoxemia were correlated with the histological features of nonalcoholic fatty liver disease (NAFLD).METHODSOne hundred twenty-six NAFLD patients who had undergone percutaneous liver biopsy were enrolled. Serum lipopolysaccharide (LPS)-binding protein (LBP) and anti-endotoxin core immunoglobulin G (EndoCab IgG) antibody concentrations at the time of liver biopsy were measured using the enzyme-linked immunosorbent assays to examine for relationships between biomarker levels and histological scores.RESULTSSerum LBP concentration was significantly increased in nonalcoholic steatohepatitis (NASH) patients as compared with nonalcoholic fatty liver (NAFL) subjects and was correlated with steatosis (r = 0.38, P < 0.0001) and ballooning scores (r = 0.23, P = 0.01), but not with the severity of lobular inflammation or fibrosis. Multivariate linear regression analysis revealed that LBP was associated with steatosis score and circulating C-reactive protein, aspartate aminotransferase, and fibrinogen levels. Serum EndoCab IgG concentration was comparable between NASH and NAFL patients. No meaningful correlations were detected between EndoCab IgG and histological findings.CONCLUSIONLBP/EndoCab IgG were not correlated with lobular inflammation or fibrosis. More accurate LPS biomarkers are required to stringently assess the contribution of endotoxemia to conventional NASH.

A Microphysiological System for Studying Nonalcoholic Steatohepatitis

“…(31) Changes to intestinal permeability cause increases in LPS concentrations in the portal vein, which can enhance liver inflammation and disease progression. (32) We therefore explored how both fat and repeat (chronic) low dosing of LPS play a role in enhancing the disease phenotype within the coculture NASH model. PHH, HK, and HSC microtissues were cultured from day 1 in HEP-LEAN medium (absent of additional FFAs), HEP-FAT medium or HEP-FAT + LPS medium, with the LPS dosing starting on day 8 of the culture onward ( Fig.…”

“…Comparing directly to patients is problematic, as determining accurate liver portal LPS concentration is challenging; however, it appears that very small differences in plasma LPS concentration differentiate among healthy patients and patients with steatosis and NASH. (32) Using LPS in our MPS in vitro NASH model demonstrates that a range of disease states can be created in the platform, from simple steatosis (with a PHH monoculture), through to NAFLD and NASH (with a co-culture) with enhanced inflammation, potentially enabling different aspects of the disease process to be investigated.…”

Intestinally derived bacterial products stimulate development of nonalcoholic steatohepatitis

“…elevates liver exposure to these substances; this occurs via activated macrophages, which release hepatotoxic factors by means of abnormal activation of the immune system [13]. However, studies conducted with human patients indicate that the exact mechanisms remain unclear [14,15].…”

Miglitol attenuates non‐alcoholic steatohepatitis in diabetic patients

“…Among several proposed metabolic alterations, disrupted glucose metabolism, such as insulin resistance, has been strongly associated with NAFLD/NASH pathogenesis . Indeed, the efficacy of the insulin sensitizer pioglitazone has been reported for NASH in several well‐designed controlled trials, although the adverse effects of long‐term pioglitazone treatment, such as weight gain, body fluid retention, and risk of osteoporosis, have been reported as well …”