Abstract
In 2020, a group of experts officially suggested metabolic dysfunction associated with fatty liver disease “MAFLD” as a more appropriate overarching term than NAFLD, indicating the key role of metabolism in fatty liver disease. Bdh1, as the rate-limiting enzyme of ketone metabolism, acts as an important metabolic regulator in liver. However, the role of Bdh1 in MAFLD is unclear. In this study, we used the transgenic db/db mice as a MAFLD mouse model and observed the downregulated expression of Bdh1 in fatty liver. In addition, expression of Bdh1 was also reduced by palmitic acid (PA) treatment in LO2 cells. Bdh1 knockdown led to ROS overproduction and ROS-induced inflammation and apoptosis in LO2 cells, while Bdh1 overexpression protected LO2 cells from lipotoxicity by inhibiting ROS overproduction. Mechanistically, Bdh1-mediated βOHB metabolism inhibits ROS overproduction by activation of Nrf2 through enhancement of metabolic flux composed of βOHB-AcAc-succinate-fumarate. Notably, adeno-associated virus (AAV)-mediated Bdh1 overexpression successfully reversed the hepatic function indexes, fibrosis, inflammation, and apoptosis in fatty livers from db/db mice. In conclusion, our study revealed a Bdh1-mediated molecular mechanism in pathogenesis of metabolic dysfunction related liver disease and identified Bdh1 as a novel potential therapeutic target for MAFLD.
Highlights
In 2018, the world population with NAFLD has reached 25% [1]
10–20% of NAFLD cases progress to NASH, which can progress to cirrhosis, hepatocellular carcinoma (HCC), and death [2]
Bdh1 was downregulated in livers from metabolic associated fatty liver disease (MAFLD) mouse model and palmitic acid (PA)-treated LO2 cells To investigate whether Bdh1 was involved in the pathogenesis of MAFLD, we firstly detected the expression levels of Bdh1 in normal and MAFLD patients
Summary
10–20% of NAFLD cases progress to NASH, which can progress to cirrhosis, hepatocellular carcinoma (HCC), and death [2]. An increasing number of evidence shows that the name “NAFLD” can not reflect the characteristics of widely combined metabolic disorders in patients [3]. The development of NASH is typically accompanied by factors related to metabolic syndrome, especially the presence of Obesity and T2DM [4,5,6]. In 2020, a group of experts officially renamed NAFLD metabolic associated fatty liver disease (MAFLD) to emphasize the key role of metabolic disorders [7]. Preventing the development of severe liver disease by controlling the progression of MAFLD is urgently needed
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