Mechanism of geniposide in improving free fatty acid metabolism in rats with non-alcoholic fatty liver disease

Abstract

To observe the effect of geniposide on non-alcoholic fatty liver disease (NAFLD), and discuss the mechanism of geniposide for NAFLD from the aspect of free fatty acid, forty healthy Wistar male rats were randomly divided into normal group, model group, geniposide and Xuezhikang group. The rats in normal group were fed with normal diets, and the rats in other 3 groups were given with high-fat diet for 8 weeks to induce the NAFLD models. From the week 5 to end of week 8, the rats in geniposide and Xuezhikang group were intervened with corresponding medicines. The body weight, liver wet weight, and fat weight of the rats were recorded. Visual and pathological changes in hepatic tissues were observed with HE staining. The contents of TG, FFA, FAS, AMPK, ACCase and Malonyl-CoA in hepatic tissue, contents of CHO and LDL-C in serum and activities of AST and ALT in serum were detected by using corresponding methods. The results showed that the body weight, liver wet weight, and fat weight of the rats, CHO, LDL-C, ALT and AST levels in serum, TG, FFA, FAS, ACCase and Malonyl-CoA levels in hepatic tissues of the rats in model group were significantly higher than those in normal group (P<0.01), while AMPK activity was significantly lower than that of the normal group (P<0.01), with obvious visual and pathological steatosis in hepatic tissues, and inflammatory injury occurred in model group. Compared with the model group, body weight of the rat, fat weight, levels of FFA in hepatic tissues, ALT and AST activities in serum, liver wet weight, TG, FAS, ACCase and Malonyl-CoA levels were significantly decreased in geniposide group (P<0.01), while the AMPK activity in hepatic tissues was significantly increased (P<0.05),with improvement in visual and pathological performance. Compared with the model group, liver wet weight, fat weight, TG and FFA levels in hepatic tissues, and LDL-C level in serum were significantly decreased in Xuezhikang group (P<0.05). Compared with Xuezhikang group, the body weight of rat, fat weight and FFA level in hepatic tissues were significantly lower in geniposide group (P<0.01), but with no significant difference in other aspects. These findings indicated that geniposide was highly effective in improving the pharmacological effect of NAFLD induced by high-fat diet, and the mechanism was achieved through AMPK-ACCase-Malonyl-CoA-FFA axis.

Protective Effect and Mechanism of Plant-Based Monoterpenoids in Non-alcoholic Fatty Liver Diseases

“…Geniposide and its aglycon genipin have been well-studied with regard to hepatic protection because geniposide-rich Gardenia fruits have been used for many years in Chinese medicine for treating hepatic disorders and inflammatory diseases. 74 In our review, we found that their effects were validated in different animal models as well as in cellular models of NAFLD or NAFLD-associated NASH and fibrosis, including tyloxapol-induced C57BL/6C mice models, 75 HFDinduced Wistar male rat models, 76 HFD-induced male Sprague Dawley rats, 77 CCl 4 -induced male Kunming mice, 78 HFDinduced male C57BL/6J mice, 79,80 HepG2 hepatocytes with FFA-induced steatosis, 81,82 and TGF-β1-induced AML12 hepatocytes. 80,83 In comparison to geniposide (25−150 mg/ kg, by oral administration), genipin (5−20 mg/kg, by oral administration) was used in a slightly lower dosage in animals possibly because of its higher bioavailability.…”

“…Further validation analysis revealed that these two compounds could inhibit liver fibrosis by detecting fibrotic gene expression and EMT marker proteins, such as hyaluronic acid, laminin, hydroxyproline, type-I collagen, PAI-1, fibronectin, E -cadherin, vimentin, Snail1, Snail2, and Twist. In addition to the above-mentioned effector molecules, the typical Nrf2/AMPK/mTOR/p-S6K, AMPK/SREBP-1c/FAS, and AMPK/ACC/CPT1 signaling pathways, participating in the regulation of oxidative stress, inflammation, energy metabolism, TGFβ/Smad or non-Smad/ERK/AKT signaling pathway, and Shh signaling pathway, participating in liver fibrosis, were regulated during geniposide and genipin intervention. − Furthermore, genipin was proven to regulate small RNAs and pyroptosis. Genipin specifically increased the expression levels of miR-142a-5p, which bound to the 3′ untranslated region of SREBP-1c to inhibit lipogenesis in HFD-induced male C57BL/6J mice .…”

Application of herbs and active ingredients ameliorate non-alcoholic fatty liver disease under the guidance of traditional Chinese medicine

“…Recent studies showed that the extract of Gardenia jasminoides J.Ellis [Rubiaceae] reduced inflammation by suppression of JNK2/1 signaling pathways ( 77 ) and the expression of cytokines such as TNF-α and IL-6 in adipose tissue ( 78 ). Moreover, active ingredients of Gardenia jasminoides J.Ellis [Rubiaceae], such as genipin and geniposide, have an alleviating effect on fatty liver in HFD-induced rat models ( 79 , 80 ). Geniposide has many biological effects, such as anti-inflammation, regulation of the amount of intestinal flora and limitation of abnormal lipid accumulation ( 10 , 81 ).…”

“…Subsequently, geniposide was found to reduce the signaling of gut-derived lipopolysaccharide (LPS), protecting the gut barrier function by down-regulating the RHOA/ROCK signaling pathway ( 81 ). Geniposide also improved hepatic free fatty acid metabolism in rats induced by a high-fat diet by regulating the AMPK–Malonyl-CoA-FFA axis ( 80 ).…”

The Beneficial Effects of Geniposide on Glucose and Lipid Metabolism: A Review

“…Geniposide is highly effective in inhibiting lipogenesis and free fatty acid (FFA) levels in hepatic tissues were decreased significantly after geniposide treatment, whereas TG, FASN, ACaCa, and malonyl-CoA levels were significantly reduced in the geniposide group. 65 Geniposide could significantly suppress hepatic total triglyceride (TG), total cholesterol (TC), and FFA in NAFLD rodents. 66 Geniposide also decreases the expression of SREBP-1c.…”