PGC-1\u03b2 Induces Susceptibility To Acetaminophen-Driven Acute Liver Failure

Elena Piccinin,Elena Bellafante,Claudia Peres,Simon Ducheix,Gaetano Villani,Maria Arconzo,Antonio Moschetta,Maria Carmela Vegliante,Anna Ferretta

doi:10.1038/s41598-019-53015-6

Abstract

Acetaminophen (APAP) is a worldwide commonly used painkiller drug. However, high doses of APAP can lead to acute hepatic failure and, in some cases, death. Previous studies indicated that different factors, including life-style and metabolic diseases, could predispose to the risk of APAP-induced liver failure. However, the molecular process that could favor APAP hepatotoxicity remains understood. Here, we reported that a short-term high fat-enriched diet worsens APAP-induced liver damage, by promoting liver accumulation of lipids that induces the activation of peroxisome proliferator-activated receptor gamma coactivator 1-beta (PGC-1β). Therefore, we challenged mice with hepatic-specific PGC-1β overexpression on a chow diet with a subtoxic dose of APAP and we found that PGC-1β overexpression renders the liver more sensitive to APAP damage, mainly due to intense oxidative stress, finally ending up with liver necrosis and mice death. Overall, our results indicated that during high fat feeding, PGC-1β adversely influences the ability of the liver to overcome APAP toxicity by orchestrating different metabolic pathways that finally lead to fatal outcome.

Highlights

Overdose of Acetaminophen (APAP) is the most frequent cause of acute and severe liver injury in the Western Countries
We reported here our results identifying the peroxisome proliferator-activated receptor gamma coactivator 1-beta (PGC-1β) as an important contributor to APAP-induced hepatic failure
The coregulator PGC-1β belongs to the PGC-1s family, whose members play a key role in the control of energy metabolism in many tissues and have been so far recognized as master regulators of mitochondrial biogenesis and antioxidant response[10,11,12,13]

Summary

Introduction

Overdose of Acetaminophen (APAP) is the most frequent cause of acute and severe liver injury in the Western Countries. Under APAP overdose conditions, a GSH severe depletion together with a significant increase of NAPQI occurs, leading to mitochondrial dysfunction, ATP depletion, oxidative stress, DNA damage and, cell death. One of the factors that can increase the risk and the severity of APAP-induced liver injury is malnutrition and related metabolic diseases. The APAP hepatotoxicity seems to be more frequent in obese or NAFLD (Non-Alcoholic Fatty Liver Disease) patients, even if some studies reported contradictory results, in which obese subjects show similar or decreased risk of APAP-induced hepatic injury compared to non-obese one[6,7,8,9]. The identification of pathophysiological molecular factors implied in APAP hepatoxicity is mandatory in order to prevent unintentional hazards to the health of users To address this issue, we reported here our results identifying the peroxisome proliferator-activated receptor gamma coactivator 1-beta (PGC-1β) as an important contributor to APAP-induced hepatic failure. By using a gain of function mouse model, we unravel the knot of an intricate scenario where PGC-1β is the mastermind able to orchestrate different hepatocellular processes that increase APAP sensitivity, leading to acute hepatic failure

Methods

Results

Conclusion