A Potential Treatment For Nonalcoholic Steatohepatitis

Contact: Audrey Hu Whatsapp/hp: 0086 13880143964 Email: audrey.hu@wecistanche.com

Nonalcoholic steatohepatitis (NASH) is associated with high levels of cholesterol and triglycerides in the liver, however, there is still no approved medical treatment. Cholesterol and triglyceride synthesis is controlled by the sterol regulatory element-binding protein (SREBP), which is abnormally activated in NASH(Nonalcoholic steatohepatitis) patients.

On January 31, 2022, Baoliang Song from Wuhan University, Wei Qi from Shanghai University of Science and Technology, and Rao Yu from Tsinghua University published a joint communication titled "Discovery of an INSIG binding compound that ameliorates nonalcoholic steatohepatitis by inhibiting SREBP-mediated SREBP-mediated" in Hepatology (IF=17). lipogenesis", which identified a potent SREBP inhibitor, 25-hydroxy lanosterol (25-HL). 25-HL binds to insulin-inducible gene (INSIG) protein, stimulates the interaction between INSIG and SCAP and retains them in the endoplasmic reticulum, thereby inhibiting SREBP activation and inhibiting adipogenesis. In a mouse model of NASH(Nonalcoholic steatohepatitis), 25-HL reduced cholesterol and triglyceride levels in serum and liver, increased energy expenditure to prevent obesity, and improved insulin sensitivity. 25-HL significantly improves liver steatosis, inflammation, ballooning, and fibrosis by downregulating the expression of lipogenic genes. Furthermore, 25-HL exhibited prophylactic and therapeutic efficacy in alleviating NASH(Nonalcoholic steatohepatitis) and atherosclerosis in ALMN diet-treated Ldlr-/- mice, and reduced cholesterol crystal formation and associated coronary structures of Kupffer cells. Notably, 25-HL reduced serum and liver lipid levels more than lovastatin or robotic folic acid. 25-HL showed a favorable safety and pharmacokinetic profile.

In conclusion, this study provides proof of concept that inhibiting SREBP activation by targeting INSIG for lipid-lowering may be a promising strategy for the treatment of NASH(Nonalcoholic steatohepatitis). This study demonstrates the translational potential of 25-HL in human NASH(Nonalcoholic steatohepatitis) and demonstrates the critical role of SREBP-controlled adipogenesis in NASH(Nonalcoholic steatohepatitis) progression through pharmacological inhibition.

Herba cistanche benefits: Lowering blood lipids and reducing inflammation and fibrosis

Nonalcoholic fatty liver disease (NAFLD) is a spectrum of liver diseases ranging from benign hepatic steatosis to malignant nonalcoholic steatohepatitis (NASH), characterized by liver damage, inflammation, and fibrosis in addition to steatosis. NASH(Nonalcoholic steatohepatitis) can further develop into cirrhosis and hepatocellular carcinoma (HCC). However, the pathogenesis of NASH(Non-alcoholic steatohepatitis) is not well understood, and there are no approved drugs to treat it.

Abnormal accumulation of triglycerides in the liver plays an important role in both the initiation and progression of NAFLD. Furthermore, recent studies have shown that deposited cholesterol, especially non-esterified cholesterol, is even more harmful than triglycerides and fatty acids in promoting the transition from simple steatosis to NASH(Nonalcoholic steatohepatitis). Excess cholesterol and fatty acids in hepatocytes trigger endoplasmic reticulum (ER) stress, leading to mitochondrial dysfunction, leading to cell death, inflammation, and fibrosis. The synthesis of cholesterol, triglycerides, and fatty acids is tightly regulated by the transcription factors sterol regulatory element-binding proteins (SREBPs, including SREBP-1a, SREBP-1c, and SREBP-2).

Precursor SREBP (pSREBP) is an ER membrane protein that binds constitutively to the ER-localized SREBP cleavage activator protein (SCAP). When cells are deprived of cholesterol, SCAP is recognized by the COPII complex and escorts SREBP to the Golgi, where it is subsequently cleaved by site 1 protease (S1P) and site 2 proteases (S2P), and finally, the N-terminal transcription factor domain is released for nuclear translocation. This karyotype SREBP (nSREBP) binds to the SRE and activates target gene expression. On the other hand, when cholesterol accumulates in the ER, the SCAP-SREBP complex is retained in the ER by binding to INSIG, so the activation of SREBP is blocked.

The benefit of desertliving cistanche: protect and nourish liver

INSIG is an ER-anchored protein that plays a central role in feedback regulation of SREBP processing by retaining the SCAP-SREBP complex in the ER. There are two INSIG proteins in mammals: INSIG-1 and INSIG-2. Both INSIGs consist of six transmembrane helices, most of which are embedded in the ER membrane, which likewise regulate SREBP processing. In addition to cholesterol, 25-hydroxycholesterol (25-HC) is a more potent inhibitor of the SREBP pathway. Unlike cholesterol binding to SCAP, recent structural studies have shown that 25-HC directly binds to the INSIG or INSIG-SCAP interface and induces SCAP-INSIG interaction.

Previous studies have shown that the rate of lipogenesis, the expression levels of lipogenic genes, and its master regulator SREBP-2 are significantly increased in both hepatic steatosis and NASH(Nonalcoholic steatohepatitis) patients. Meanwhile, NASH(Nonalcoholic steatohepatitis) patients had higher levels of SREBP-2 and cholesterol synthesis than patients with simple steatosis. A similar phenomenon of increased adipogenesis and activated SREBP-1c was observed in a mouse model of NAFLD. Aberrant activation of SREBP induced by ER stress has been shown to drive adipogenesis and NASH(Nonalcoholic steatohepatitis). Conversely, knockout of hepatic Scap reduced lipid levels in the liver and blood. Therefore, inhibiting lipogenesis by inhibiting the SREBP pathway may be an effective strategy for the treatment of hepatic steatosis and NASH(Nonalcoholic steatohepatitis).

In this study, a potent and specific inhibitor of the SREBP pathway, 25-hydroxyl lanosterol (25-HL), was identified but did not activate the liver X receptor (LXR). Furthermore, this study elucidates the mechanism of directly targeting INSIGs to block SREBP-processed 25-HL and evaluates its preventive and therapeutic effects in the treatment of NASH(Nonalcoholic steatohepatitis) in a mouse model.

Cistanche extract for kidney nourishment

This study identified a potent SREBP inhibitor, 25-hydroxyl anosterol (25-HL). 25-HL binds to insulin-inducible gene (INSIG) protein, stimulates the interaction between INSIG and SCAP and retains them in the endoplasmic reticulum, thereby inhibiting SREBP activation and inhibiting adipogenesis. In a mouse model of NASH(Nonalcoholic steatohepatitis), 25-HL reduced cholesterol and triglyceride levels in serum and liver, increased energy expenditure to prevent obesity, and improved insulin sensitivity. 25-HL significantly improves liver steatosis, inflammation, ballooning, and fibrosis by downregulating the expression of lipogenic genes. Furthermore, 25-HL exhibited prophylactic and therapeutic efficacy in alleviating NASH(Nonalcoholic steatohepatitis) and atherosclerosis in ALMN diet-treated Ldlr-/- mice, and reduced cholesterol crystal formation and associated coronary structures of Kupffer cells. Notably, 25-HL reduced serum and liver lipid levels more than lovastatin or robotic folic acid. 25-HL showed a favorable safety and pharmacokinetic profile.

In conclusion, this study provides proof of concept that inhibiting SREBP activation by targeting INSIG for lipid-lowering may be a promising strategy for the treatment of NASH(Nonalcoholic steatohepatitis). This study demonstrates the translational potential of 25-HL in human NASH(Nonalcoholic steatohepatitis) and demonstrates the critical role of SREBP-controlled adipogenesis in NASH(Nonalcoholic steatohepatitis) progression through pharmacological inhibition.

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cistanche tubolosa extract: anti-inflammation