Metabolic associated fatty liver disease (MAFLD) which is a condition closely linked to type 2 diabetes, obesity, hyperlipidemia, and other metabolic disorders, has posed a significant threat to human health and caused a huge economic burden to society (Eslam et al., 2020). In MAFLD, hepatic steatosis is attributable to lipid acquisition exceeding lipid disposal, including the excessive uptake of fatty acids, overload of de novo lipogenesis, and the inhibition of fatty acids oxidation and export. The most common approach to MAFLD treatment was dietary and lifestyle changes. The clinical development of drugs encompasses antidiabetic agents (Mengwei Li et al., 2022), farnesoid X receptor agonists (Clifford et al., 2021), peroxisome proliferator-activated receptors agonists (Filipovic et al., 2023), thyroid hormone receptor agonists (Caddeo et al., 2021), and other pharmaceuticals. However, no FDA-approved medications are efficacious in the treatment of MAFLD. The increase of fatty acid oxidation is a known method for its treatment (Reddy and Rao, 2006). The main sites of fatty acid β-oxidation include mitochondria and peroxisomes. Therein, peroxisomes have irreplaceable functions that oxidize long-chain fatty acids (LCFAs, C12∼C20), very-long-chain fatty acids (VLCFAs, C>20), dicarboxylic acids (DCA), and bile acid intermediates (Reddy and Hashimoto, 2001). LCFAs are the main materials for the synthesis of triglycerides (TG) (Berk and Verna, 2016, Younossi et al., 2021). It has been established that increased LCFAs entry into hepatocytes can induce apoptosis, oxidative stress, and chronic inflammatory responses in hepatocytes with steatosis (Pedersen et al., 2023). However, there have been no therapeutic strategies for regulating LCFAs in MAFLD.
Tamoxifen (TMX), a nonsteroidal antiestrogen, is one of the most extensively used drugs to treat breast cancer (Barzaman et al., 2020, Reinert and Barrios, 2015). Since TMX was approved for the treatment of breast cancer in 1973, TMX treatment has significantly reduced the recurrence of breast cancer and improved the survival rate of breast cancer patients (Jordan, 1992). Although clinical data have shown that the prevalence of TMX-induced fatty liver is 40.25% (Allard et al., 2019), some other reports have shown contracts. A study demonstrated that TMX exerted a hepatoprotective effect against steatosis and non-alcoholic steatohepatitis (NASH) in mouse models (Miyashita, 2012). Likewise, TMX decreased hepatic TG, and serum total cholesterol (TC) contents in a high-fat diet (HFD)-induced metabolic disordered model through JNK/MAPK inhibition (Fang et al., 2023). The contradictory results were also shown in vitro research. David Grünig (Grunig et al., 2018) found that TMX could inhibit the activity of CPT1α, thereby inhibiting mitochondrial β-oxidation in HepG2 cells. However, in Fei Zhao’s (Zhao et al., 2014) research, there was no change in CPT1 expression in response to TMX in HepG2 cells. To date, the relationship between TMX and lipid metabolism has been unclear.
Enoyl CoA hydratase and 3-hydroxyacyl CoA hydratase (EHHADH) also known as L-peroxisomal bifunctional enzyme (L-PBE) is one of the enzymes of peroxisome β-oxidation and is highly expressed in the liver and kidney (Ding et al., 2013, Houten et al., 2012, Uhlen et al., 2015). There are four enzymatic steps in the cycle of peroxisomal β-oxidation: dehydrogenation, hydration, dehydrogenation again, and thiolytic cleavage (Wanders et al., 2001, Wanders and Waterham, 2006). EHHADH catalyzes the second and third steps of peroxisomal β-oxidation, along with the other enzyme D-peroxisomal bifunctional enzyme (Reddy and Hashimoto, 2001). However, there has been no research on the influence of EHHADH activation on LCFAs metabolism. It is worth investigating whether peroxisome β-oxidation plays a role in the influence of TMX on lipid metabolism.
In this study, we investigated the influence of TMX on fatty acid metabolism. This research focused on the effect of TMX on peroxisome β-oxidation in the liver and proposed a new explanation for the influence of TMX on lipid metabolism. Furthermore, it might provide a method for the treatment of MAFLD.