Digeda-4 decoction and its disassembled prescriptions improve dyslipidemia and apoptosis by regulating AMPK/SIRT1 pathway on tyloxapol-induced nonalcoholic fatty liver disease in mice

by Selleckchem | Oct 28 2023

Ethnopharmacological relevance: Nonalcoholic fatty liver disease (NAFLD) is a manifestation of metabolic syndrome in the liver and the leading cause of chronic liver disease worldwide. Digeda-4 decoction (DGD-4) is a commonly prescribed Mongolian herbal drug for treating acute and chronic liver injury and fatty liver. However, the mechanisms underlying the improvement of dislipidemia and liver injury via treatment with DGD-4 remain unclear. Disassembling a prescription is an effective approach to studying the effects and mechanisms underlying Mongolian medicine prescriptions. By disassembling a prescription, it is feasible to discover effective combinations of individual herbs to optimize a given prescription. Accordingly, we disassembled DGD-4 into two groups: the single Lomatogonium rotatum (L.) Fries ex Nym (LR) (DGD-1) and non-LR (DGD-3).

Aim of this study: To study whether DGD-4 and its disassembled prescriptions have protective effects against tyloxapol (TY)-induced NAFLD and to explore the underlying mechanisms of action and compatibility of prescriptions.

Material and methods: NAFLD mice were developed by TY induction. Biochemical horizontal analyses, enzyme-linked immunosorbent assay, and liver histological staining were performed to explore the protective effects of DGD-4 and its disassembled prescriptions DGD-3 and DGD-1. Furthermore, we performed immunohistochemical analyses and Western blotting to further explore the expression of target proteins.

Results: DGD-4 and its disassembled prescriptions could inhibit TY-induced dislipidemia and liver injury. In addition, DGD-4 and its disassembled prescriptions increased the levels of p-AMPKα and p-ACC, but decreased the levels of SREBP1c, SCD-1, SREBP-2, and HMGCS1 proteins. The activation of lipid metabolic pathways SIRT1, PGC-1α, and PPARα improved lipid accumulation in the liver. Moreover, DGD-4 could inhibit hepatocyte apoptosis and treat TY-induced liver injury by upregulating the Bcl-2 expression, downregulating the expression of Bax, caspase-3, caspase-8, and the ratio of Bax/Bcl-2, and positively regulating the imbalance of oxidative stress (OxS) markers (such as superoxide dismutase [SOD], catalase [CAT], malondialdehyde [MDA], and myeloperoxidase [MPO]). DGD-1 was superior to DGD-3 in regulating lipid synthesis-related proteins such as SREBP1c, SCD-1, SREBP-2, and HMGCS1. DGD-3 significantly affected the expression of lipid metabolic proteins SIRT1, PGC-1α, PPARα, apoptotic proteins Bcl-2, Bax, caspase-3, caspase-8, and the regulation of Bax/Bcl-2 ratio. However, DGD-1 showed no regulatory effects on Bax and Bcl-2 proteins.

Conclusion: This study demonstrates the protective effects of DGD-4 in the TY-induced NAFLD mice through a mechanism involving improvement of dyslipidemia and apoptosis by regulating the AMPK/SIRT1 pathway. Although the Monarch drug DGD-1 reduces lipid accumulation and DGD-3 inhibits apoptosis and protects the liver from injury, DGD-4 can be more effective overall as a therapy when compared to DGD-1 and DGD-3.

Comments:

The study you mentioned investigated the effects and mechanisms of Digeda-4 decoction (DGD-4), a Mongolian herbal drug, in the treatment of nonalcoholic fatty liver disease (NAFLD) in mice. NAFLD is a prevalent liver disease associated with metabolic syndrome. DGD-4 has been traditionally used to treat liver injury and fatty liver in Mongolian medicine. In this study, the researchers disassembled DGD-4 into two groups: DGD-1, which contained a single herb called Lomatogonium rotatum (L.) Fries ex Nym (LR), and DGD-3, which consisted of the remaining herbs.

The aim of the study was to determine if DGD-4 and its disassembled prescriptions (DGD-1 and DGD-3) have protective effects against NAFLD induced by tyloxapol (TY) and to investigate the underlying mechanisms of action and prescription compatibility.

The researchers conducted various analyses and assays to evaluate the protective effects of DGD-4, DGD-1, and DGD-3. They examined biochemical markers, performed enzyme-linked immunosorbent assays, and conducted liver histological staining. Additionally, immunohistochemical analyses and Western blotting were used to assess the expression of specific proteins related to the observed effects.

The results of the study showed that both DGD-4 and its disassembled prescriptions (DGD-1 and DGD-3) could inhibit TY-induced dyslipidemia (abnormal lipid levels) and liver injury. These formulations increased the levels of phosphorylated AMPKα and ACC proteins while decreasing the levels of SREBP1c, SCD-1, SREBP-2, and HMGCS1 proteins. Activation of lipid metabolic pathways involving SIRT1, PGC-1α, and PPARα led to improved lipid accumulation in the liver.

Furthermore, DGD-4 exhibited anti-apoptotic effects and effectively treated TY-induced liver injury by upregulating Bcl-2 expression, downregulating the expression of Bax, caspase-3, and caspase-8, and positively regulating the oxidative stress markers SOD, CAT, MDA, and MPO. DGD-1 was more effective than DGD-3 in regulating lipid synthesis-related proteins, whereas DGD-3 had a significant impact on the expression of lipid metabolic proteins and apoptotic proteins.

In conclusion, the study demonstrated the protective effects of DGD-4 in TY-induced NAFLD mice. The underlying mechanism involved the regulation of dyslipidemia and apoptosis through the AMPK/SIRT1 pathway. Although DGD-1 reduced lipid accumulation and DGD-3 inhibited apoptosis and protected the liver from injury, DGD-4 was found to be more effective overall in the treatment of NAFLD when compared to DGD-1 and DGD-3.