Lipoprotein Z, a hepatotoxic lipoprotein, predicts outcome in alcohol‐associated hepatitis

Abstract

Background and Aims: Lipoprotein Z (LP-Z) is an abnormal free cholesterol (FC)-enriched LDL-like particle discovered from patients with cholestatic liver disease. This study aims to define the diagnostic value of LP-Z in alcoholassociated hepatitis (AH) and interrogate the biology behind its formation. Approach and Results:We measured serum levels of LP-Z using nuclear magnetic resonance spectroscopy, a well-established clinical assay. Serum levels of LP-Z were significantly elevated in four AH cohorts compared with control groups, including heavy drinkers and patients with cirrhosis. We defined a Z-index, calculated by the ratio of LP-Z to total apolipoprotein B-containing lipoproteins, representing the degree of deviation from normal VLDL metabolism. A high Z-index was associated with 90-day mortality independent from the Model for End-Stage Liver Disease (MELD) and provided added prognosticative value. Both a Z-index ≤ 0.6 and a decline of Z-index by ≥0.1 in 2 weeks predicted 90-day survival. RNA-sequencing analyses of liver tissues demonstrated an inverse association in the expression of enzymes responsible for the extrahepatic conversion of VLDL to LDL and AH disease severity, which was further confirmed by the measurement of serum enzyme activity. To evaluate whether the FC in LP-Z could contribute to the pathogenesis of AH, we found significantly altered FC levels in liver explant of patients with AH. Furthermore, FC in reconstituted LP-Z particles caused direct toxicity to human hepatocytes in a concentration-dependent manner, supporting a pathogenic role of FC in LP-Z.

Profoundly Disturbed Lipoproteins in Cirrhotic Patients: Role of Lipoprotein-Z, a Hepatotoxic LDL-like Lipoprotein

“…Patients with cirrhotic end-stage liver disease have lower levels of circulating LCAT, besides alterations in CETP and HL activities [ 9 ], which raises the possibility that defective lipoprotein remodeling and catabolism may contribute to the generation of LP-Z in cirrhosis [ 9 , 49 ]. Very recently, it was suggested that compromised LCAT and HL activities may at least in part be responsible for the high prevalence of plasma LP-Z in alcoholic hepatitis [ 59 ]. Moreover, free cholesterol-rich reconstituted LP-Z particles were found to be hepatotoxic, as evidenced by the accelerated death of cultured hepatocytes from liver explants [ 59 ].…”

“…Very recently, it was suggested that compromised LCAT and HL activities may at least in part be responsible for the high prevalence of plasma LP-Z in alcoholic hepatitis [ 59 ]. Moreover, free cholesterol-rich reconstituted LP-Z particles were found to be hepatotoxic, as evidenced by the accelerated death of cultured hepatocytes from liver explants [ 59 ]. These findings suggest that LP-Z itself could have detrimental effects on the progression of liver disease.…”

“…In the report of LP-Z in alcoholic hepatitis, LP-Z expressed as the ratio of LP-Z over VLDL + LDL apoB predicted a worse 90-day survival taking account of the MELD score [ 59 ]. In the current study, LP-Z was more closely related to the MELD score than to the CPT classification.…”