Caveolin-1 Alleviates Acetaminophen-Induced Fat Accumulation in Non-Alcoholic Fatty Liver Disease by Enhancing Hepatic Antioxidant Ability via Activating AMPK Pathway.

Jiarong Wang,Wei Jiang,Jiao Xin,Congjian Shi,Yan Huang,Weiju Xue,Jiagen Wen,Chengmu Hu

doi:10.3389/fphar.2021.717276

Abstract

Non-alcoholic fatty liver disease (NAFLD) is an independent risk factor for acute liver injury caused by overuse of acetaminophen (APAP). Caveolin-1 (CAV1), a regulator of hepatic energy metabolism and oxidative stress, was found to have a protective effect against NAFLD in our previous study. However, it remains unclear whether CAV1 has a protective effect against APAP-induced hepatotoxicity in NAFLD. The aim of this study was to determine whether CAV1 inhibits oxidative stress through the AMPK/Nrf2/HO-1 pathway to protect the liver from fat accumulation exacerbated by APAP in NAFLD. In this study, seven-week-old C57BL/6 male mice (18–20 g) were raised under similar conditions for in vivo experiment. In vitro, L02 cells were treated with A/O (alcohol and oleic acid mixture) for 48 h, and APAP was added at 24 h for further incubation. The results showed that the protein expression of the AMPK/Nrf2 pathway was enhanced after CAV1 upregulation. The effects of CAV1 on fat accumulation, ROS, and the AMPK/Nrf2 anti-oxidative pathway were reduced after the application of CAV1-siRNA. Finally, treatment with compound C (an AMPK inhibitor) prevented CAV1 plasmid-mediated alleviation of oxidative stress and fat accumulation and reduced the protein level of Nrf2 in the nucleus, demonstrating that the AMPK/Nrf2/HO-1 pathway was involved in the protective effect of CAV1. These results indicate that CAV1 exerted a protective effect against APAP-aggravated lipid deposition and hepatic injury in NAFLD by inhibiting oxidative stress. Therefore, the upregulation of CAV1 might have clinical benefits in reducing APAP-aggravated hepatotoxicity in NAFLD.

Highlights

Acetaminophen (APAP) is one of the most commonly used antipyretic and analgesic over-the-counter (OTC) drugs worldwide
These results indicated that CSD effectively reduced APAP-aggravated hepatic injury and lipid deposition in Non-alcoholic fatty liver disease (NAFLD)
CAV1 silencing decreased the protein levels of p-AMPK and HO-1 (Figure 8A) and reduced the expression of Nrf2 in the nucleus (Figure 8B). These results demonstrate that the protective effect of CAV1 on APAP-induced liver injury in NAFLD may be associated with activation of the AMPK/Nrf2dependent pathway

Summary

Introduction

Acetaminophen (APAP) is one of the most commonly used antipyretic and analgesic over-the-counter (OTC) drugs worldwide. Its long-term use or overdose of APAP is the most common cause of acute liver failure and intentional or accidental death in the northern hemisphere (Lee, 2017). Long-term APAP ingestion has been reported to aggravate chronic liver injury in some patients, including NAFLD (Michaut et al, 2014). Clinical and experimental evidence demonstrates that excessive APAP consumption in NAFLD aggravates risk and severity of hepatic injury (Michaut et al, 2014; Arconzo et al, 2021). The effect of steatosis on drug toxicity remains controversial, it is worth noting that a recent study showed that a high-fat diet (HFD) can induce the expression of drug-metabolizing enzymes (including CYP2E1) in the liver of C57BL/6 male mice (Wang et al, 2020), which may be responsible for the vulnerability of NAFLD to APAP. More specific pharmacological treatment need be fully explored and established

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