Bdh1 overexpression ameliorates hepatic injury by activation of Nrf2 in a MAFLD mouse model

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.

D-β-Hydroxybutyrate Dehydrogenase Mitigates Diabetes-Induced Atherosclerosis through the Activation of Nrf2

“…39 Xu et al found that the overexpression of Bdh1 could attenuate high-fat diet-induced liver damage by inhibiting oxidative stress and apoptosis. 40 Our results showed that Bdh1 overexpression reduced oxidative stress and inflammatory responses in macrophages and that AAV-mediated Bdh1 overexpression reduced vascular inflammatory responses. It has been hypothesized that Bdh1 exerts a protective effect against diabetes and AS by inhibiting oxidative stress.…”

Emerging Role of Hepatic Ketogenesis in Fatty Liver Disease

“…In support of this concept, Xu et al demonstrated that the increase in NASH characteristics upon Bdh1 knockdown is associated with increased ROS levels (Xu et al, 2022). Conversely, Bdh1 overexpression successfully attenuated lipotoxicity, oxidative stress-induced hepatic injury, inflammation and apoptosis in the fatty liver from db/db mice (Xu et al, 2022). Additionally, several lines of evidence support the concept that hepatic ketogenesis might regulate NASH phenotype through mitochondrial metabolism and inflammation.…”

“…Elevated ROS causes hepatocellular damage by inducing DNA damage and increasing the accumulation of toxic lipids and proteins (Rolo et al, 2012;Masarone et al, 2018). In support of this concept, Xu et al demonstrated that the increase in NASH characteristics upon Bdh1 knockdown is associated with increased ROS levels (Xu et al, 2022). Conversely, Bdh1 overexpression successfully attenuated lipotoxicity, oxidative stress-induced hepatic injury, inflammation and apoptosis in the fatty liver from db/db mice (Xu et al, 2022).…”

Identifying key multifunctional components shared by critical cancer and normal liver pathways via SparseGMM

“… 54 Moreover, Bdh1 overexpression ameliorates hepatic injury in a metabolic-associated fatty liver disorder (MAFLD) mouse model. 55 These findings point to SparseGMM-identified hepatic differentiation and metabolism genes as potential bona fide transcriptional biomarkers of hepatic differentiation and metabolism in healthy livers.…”