The Beneficial Additive Effect of Silymarin in Metformin Therapy of Liver Steatosis in a Pre-Diabetic Model

Abstract

The combination of plant-derived compounds with anti-diabetic agents to manage hepatic steatosis closely associated with diabetes mellitus may be a new therapeutic approach. Silymarin, a complex of bioactive substances extracted from Silybum marianum, evinces an antioxidative, anti-inflammatory, and hepatoprotective activity. In this study, we investigated whether metformin (300 mg/kg/day for four weeks) supplemented with micronized silymarin (600 mg/kg/day) would be effective in mitigating fatty liver disturbances in a pre-diabetic model with dyslipidemia. Compared with metformin monotherapy, the metformin–silymarin combination reduced the content of neutral lipids (TAGs) and lipotoxic intermediates (DAGs). Hepatic gene expression of enzymes and transcription factors involved in lipogenesis (Scd-1, Srebp1, Pparγ, and Nr1h) and fatty acid oxidation (Pparα) were positively affected, with hepatic lipid accumulation reducing as a result. Combination therapy also positively influenced arachidonic acid metabolism, including its metabolites (14,15-EET and 20-HETE), mitigating inflammation and oxidative stress. Changes in the gene expression of cytochrome P450 enzymes, particularly Cyp4A, can improve hepatic lipid metabolism and moderate inflammation. All these effects play a significant role in ameliorating insulin resistance, a principal background of liver steatosis closely linked to T2DM. The additive effect of silymarin in metformin therapy can mitigate fatty liver development in the pre-diabetic state and before the onset of diabetes.

Guanidinoacetic acid ameliorates hepatic steatosis and inflammation and promotes white adipose tissue browning in middle-aged mice with high-fat-diet-induced obesity

“…49 It has been reported that SREBP1, a member of the SREBP family, is primarily involved in regulating cholesterol, fatty acids, and triglycerides and is considered to be responsible for controlling lipid metabolism homeostasis in animals. 50 Increasing evidence has demonstrated that some bioactive substances, such as silymarin, 51 ginsenoside Rg1, 52 and naringin, 53 can alleviate HFD-induced hepatic steatosis by inhibiting the expression of PPARγ and SREBP-1c in the liver. Similar results were found in our study: the GAA supplementation noticeably reduced the levels of PPARγ and SREBP-1c in HFD-fed mice, implying that GAA mitigates HFD-induced hepatic steatosis and lipid synthesis.…”

The effect of medicinal plants on cirrhosis: A systematic review of clinical trials

“…Silymarin is one of the most important medicinal plant extracts obtained from milk thistle (Rainone, 2005) that, by improving inflammatory factors and increasing antioxidant capacity, can improve cellular damage in the liver, prevent and improve fibrosis and cirrhosis, and reduce liver damage caused by some drugs (Ali et al, 2018; Fehér & Lengyel, 2012; Kheiripour et al, 2019; Tao et al, 2019; Vargas‐Mendoza et al, 2014). Several studies have reported the therapeutic effects of silymarin in liver diseases, including fatty liver disease, hepatic steatosis, liver fibrosis, and cirrhosis (Abenavoli et al, 2018; Cacciapuoti et al, 2013; Chen et al, 2012; Colica et al, 2017; Famouri et al, 2016; Fehér & Lengyel, 2012; Hüttl et al, 2021; Kalopitas et al, 2021; Ni & Wang, 2016; Solhi et al, 2014; Tsai et al, 2008; Zhu et al, 2018).…”

Diabetes and diabesity in the view of proteomics, drug, and plant-derived remedies

“…[ 161 ] At the molecular level, the expression of transcription factors involved in lipid metabolism, such as PPARγ, and PPARα in the liver, has been postulated by Silymarin, suggesting its beneficial effects in the treatment of fatty liver. [ 162 ]…”