Ginseng Saponin Enriched in Rh1 and Rg2 Ameliorates Nonalcoholic Fatty Liver Disease by Inhibiting Inflammasome Activation

Abstract

Nonalcoholic fatty liver disease (NAFLD) is becoming one of the most common chronic liver diseases in the world. One of the features of NAFLD is hepatic fat accumulation, which further causes hepatic steatosis, fibrosis, and inflammation. Saponins, the major pharmacologically active ingredients isolated from Panax notoginseng, contain several ginsenosides, which have various pharmacological and therapeutic functions. However, the ginsenoside-specific molecular mechanism of saponins in NAFLD remains unknown. This study aimed to elucidate the effects of ginseng saponin extract and its ginsenosides on hepatic steatosis, fibrosis, and inflammation and their underlying action mechanism in NAFLD. Mice were fed a fast food diet (FFD) for 16 weeks to induce NAFLD and then treated with saponin extract (50 or 150 mg/kg) for the remaining nine weeks to determine the effects of saponin on NAFLD. Saponin extract administration significantly alleviated FFD-induced hepatic steatosis, fibrosis, and inflammation. Particularly, saponin extract, compared with conventional red ginseng, contained significantly increased amounts of ginsenosides (Rh1 (10.34-fold) and Rg2 (7.1-fold)). In vitro Rh1 and Rg2 treatments exerted an anti-steatotic effect in primary hepatocytes, an antifibrotic effect in hepatic stellate cells, and anti-inflammatory and pro-mitophagy effects in immortalized mouse Kupffer cells. Mechanistically, saponin extract alleviated lipopolysaccharide-induced NLRP3 inflammasome activation by promoting mitophagy. In conclusion, saponin extract inhibited inflammation-mediated pathological inflammasome activation in macrophages, thereby preventing NAFLD development. Thus, saponin extract administration may be an alternative method for NAFLD prevention.

The NLRP3 Inflammasome in Non-Alcoholic Fatty Liver Disease and Steatohepatitis: Therapeutic Targets and Treatment

“…In particular, saponin extract contains significantly increased amounts of ginsenosides, including Rh1 and Rg2, which cause a blockade of steatosis in hepatocytes, inhibition of fibrosis in hepatic stellate cells, and promote mitophagy in Kupffer cells. Furthermore, ginseng saponin enriched for Rh1 and Rg2 can ameliorate NAFLD by inhibiting NLRP3 inflammasome activation through promotion of mitophagy ( Wang F. et al, 2021 ). Thus, administration of ginseng saponin is likely advisable for NAFLD prevention.…”

Modulatory Properties of Food and Nutraceutical Components Targeting NLRP3 Inflammasome Activation

“…Wang et al [ 118 ] analyzed the effects of saponins isolated from Panax notoginseng in ameliorating NLFD through inhibition of inflammasome activation. The saponin extract, compared with conventional red ginseng, contained significantly increased amounts of ginsenosides Rh1 (10.34-fold) and Rg2 (7.1-fold), which are the main components highlighting the pharmacological activity of ginseng.…”

Potential benefits of ginseng against COVID-19 by targeting inflammasomes

“…Numerous ginsenosides and ginseng saponins have been demonstrated to inhibit NLRP3 inflammasome activation, resulting in the suppression of inflammatory responses and amelioration of disease conditions. Rb1, Rg1, Rg2, Rg3, Rg5, Rd, Re, Rh1, 25-OCH 3 -PPD, and compound K (CK) in Panax ginseng inhibit NLRP3 inflammasome stimulation, leading to suppressed inflammatory responses and multiple disease conditions, such as obesity, gouty arthritis, atherosclerosis , non-alcoholic fatty liver disease, liver injury, hyperlipidemia, type I diabetes, myocardial hypertrophy and dysfunction, cerebral ischemia and reperfusion injury, colitis, hepatic fibrosis, sepsis, neuronal damage, kidney injury, and cognitive deficits [ [55] , [56] , [57] , [58] , [59] , [60] , [61] , [62] , [63] , [64] , [65] , [66] , [67] , [68] , [69] , [70] , [71] , [72] , [73] ]. Korean red ginseng (KRG) extract and KRG saponin fraction in Panax ginseng also inhibited inflammatory responses by inhibiting NLRP3 inflammasome activation in macrophages, monocytes, sepsis mice, and aging mice [ 65 , 74 ].…”

“… Target Ginseng Components Models Ref. NLRP3 Panax ginseng Rb1 3T3-L1, adipose tissue [ 55 ] Gouty arthritic rats [ 56 ] Rg1 NAFLD mice [ 57 ] Liver injury mice [ 58 , 59 ] BNCC337685, diabetic nephropathy rats [ 60 ] Diabetic mice [ 61 ] Cardiomyocytes, myocardial injury mice [ 62 ] Rg2 KC, NAFLD mice [ 63 ] Rg3 RAW264.7, sepsis mice [ 64 ] BMDMs, THP-1, sepsis mice [ 65 ] HK-2, kidney injury mice [ 66 ] AC16, HCM, cardiomyocytes, myocardial hypertrophy rats [ 67 ] Rg5 Diabetic nephropathy mice [ 68 ] Rd THP-1, colitis mice [ 69 ] Cerebral IRI mice [ 70 ] Re Memory impairment mice [ 71 ] Rh1 BMDMs, THP-1, sepsis mice [ 65 ] KC, NAFLD mice [ 63 ] 25-OCH 3 -PPD HSC-T6, hepatic fibrosis mice …”