Hyperlipidemia, a metabolic disorder, is considered a risk factor for cardiovascular and cerebrovascular diseases (Xie et al., 2023). With economic development, an increasing number of individuals are experiencing hyperlipidemia due to prolonged excessive nutrient intake. Elevated serum lipid levels lead to the deposition of lipids on arterial walls, forming plaques that can contribute to various cardiovascular diseases (Hou et al., 2023). Cardiovascular disease is a predominant global cause of death, imposing a significant public health burden (Gaidai et al., 2023). Additionally, the accumulation of substantial amounts of non-metabolized lipids in the liver induces inflammation and liver injury, further exacerbating the condition (Yan et al., 2023). Consequently, the prevention and treatment of hyperlipidemia are imperative.

Low-density lipoprotein-cholesterol (LDL-C) stands out as a major risk factor for cardiovascular disease, exacerbating hyperlipidemia (Tokgozoglu and Kocyigit, 2021). Enhancing the clearance of excess LDL is an effective clinical approach to treating hyperlipidemia (Ference et al., 2017). Statins, such as rosuvastatin (RSV), are widely prescribed for dyslipidemia treatment (Xu S et al., 2021b). As inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR, EC 1.1.1.34), statins reduce body lipid levels by lowering LDL-C and triglyceride (TG) levels (Hussain et al., 2023). However, statins have inherent limitations (Chaulin, 2023). Consequently, the development of novel therapeutic drugs is imperative.

Natural remedies are increasingly utilized for the prevention and treatment of hyperlipidemia. Curcuma amada, rhubarb, and Psoralea corylifolia demonstrate significant lipid-lowering effects by inhibiting pancreatic lipase and reducing TG synthesis (Jalaja et al., 2021; Wu et al., 2023; Zhao et al., 2022). However, the active ingredients in several plant-derived compounds remain unclear.

Tetrahydroberberine (THB, C20H21NO4, 339.39, Fig. 1A), a metabolite of berberine (BBR, C20H18NO4, 336.37, Fig. 1B), exhibits a distinct lipid-lowering effect (Kong et al., 2022), and its oral bioavailability surpasses that of berberine (Feng et al., 2021; Zhang et al., 2012). It holds considerable potential for further development as an antihyperlipidemic candidate. Nonetheless, the lipid-lowering mechanism of tetrahydroberberine remains unclear and requires urgent elucidation. Berberine mitigates hypercholesterolemia by upregulating liver LDL receptor (Yang et al., 2022). The LDL receptor is regulated by peroxisome proliferator-activated receptor α (PPARα) and proprotein convertase subtilisin/kexin type 9 (PCSK9), influencing LDL clearance (Oza and Kashfi, 2023; Raha et al., 2021). Tetrahydroberberine may exert a similar effect through a hydride mechanism.

The assembly of LDL is influenced by apolipoprotein E (ApoE) and apolipoprotein B100 (ApoB100) (Hone et al., 2019; Mehta and Shapiro, 2021). This process plays a crucial role in LDL-C clearance and serves as a significant mechanism for ameliorating hyperlipidemia (Walsh and Hussain, 2016). Consequently, the current study endeavors to explore the potential protective effects of tetrahydroberberine and its underlying mechanisms against hyperlipidemia induced by a high-fat diet (HFD) in mice. This investigation involves examining alterations in lipoprotein assembly that induce changes in LDL and intermediate-density lipoprotein (IDL).