Discovering a critical transition state from nonalcoholic hepatosteatosis to nonalcoholic steatohepatitis by lipidomics and dynamical network biomarkers

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a major risk factor for type 2 diabetes and metabolic syndrome. However, accurately differentiating nonalcoholic steatohepatitis (NASH) from hepatosteatosis remains a clinical challenge. We identified a critical transition stage (termed pre-NASH) during the progression from hepatosteatosis to NASH in a mouse model of high fat-induced NAFLD, using lipidomics and a mathematical model termed dynamic network biomarkers (DNB). Different from the conventional biomarker approach based on the abundance of molecular expressions, the DNB model exploits collective fluctuations and correlations of different metabolites at a network level. We found that the correlations between the blood and liver lipid species drastically decreased after the transition from steatosis to NASH, which may account for the current difficulty in differentiating NASH from steatosis based on blood lipids. Furthermore, most DNB members in the blood circulation, especially for triacylglycerol (TAG), are also identified in the liver during the disease progression, suggesting a potential clinical application of DNB to diagnose NASH based on blood lipids. We further identified metabolic pathways responsible for this transition. Our study suggests that the transition from steatosis to NASH is not smooth and the existence of pre-NASH may be partially responsible for the current clinical limitations to diagnose NASH. If validated in humans, our study will open a new avenue to reliably diagnose pre-NASH and achieve early intervention of NAFLD.

Serum Monounsaturated Triacylglycerol Predicts Steatohepatitis in Patients with Non-alcoholic Fatty Liver Disease and Chronic Hepatitis B

“…Previous studies revealed lipidomic signatures in the liver and the serum of patients with NAFLD 15 – 17 , and its possibility of non-invasive approach diagnosing NASH 2 , 3 . However, there were few studies of serum lipidomic profiles in CHB and of the biomarkers in the diagnosis of NASH in patients with active chronic viral hepatitis.…”

“…The gold standard of diagnosis of NASH depends on liver biopsy. Recent study has shown that serum lipid and molecular metabolites could be used to differentiate between non-alcoholic fatty liver (NAFL) and NASH 2 , 3 . The noninvasive strategies for the diagnosis of NASH by lipidomic approach remained great clinical importance.…”

Mitochondrial dysfunction-related lipid changes occur in nonalcoholic fatty liver disease progression

“…this has proven to be very difficult because the correlations between blood and liver lipid species drastically decrease after the transition from NAFL to NASH (5). We previously used lipidomics to compare serum lipid profiles from excessive chronic drinkers without liver disease to those with advanced alcoholic cirrhosis, and showed that circulating lipids associate with alcoholic liver cirrhosis and represent potential biomarkers for risk assessment (6).…”

Low-Grade Dysplastic Nodules Revealed as the Tipping Point during Multistep Hepatocarcinogenesis by Dynamic Network Biomarkers

“…Therefore, the three conditions are considered as the generic properties to detect early-warning signals of the pre-disease state or critical state. Note that DNB is a functional module, which signals the imminent transition or deterioration from the normal state to the disease state, and, therefore, is considered to be causally related to the initiation and progression of the disease [ 12 , 13 , 17 , 18 ].…”