Hepatic Reduction in Cholesterol 25-Hydroxylase Aggravates Diet-induced Steatosis

Dong, Zeyu; He, Fangzhou; Yan, Xiaosong; Yang, Xing; Lei, Yuyang; Gao, Jie; He, Ming; Li, Dongmin; Bai, Liang; Yuan, Zuyi; Shyy, John Y.‐J.

doi:10.1016/j.jcmgh.2021.12.018

Cited by 13 publications

(6 citation statements)

References 43 publications

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“…In terms of the process, HFD stimulates BA secretion to facilitate fat digestion [ 29 , 30 ], which is a major reason that ileal Fxr/Shp/Fgf15 signaling was remarkably increased in mice, regardless of tumor metastasis. Unlike previous findings that HFD hinders BA synthesis [ 31 , 32 ], our data revealed that HFD resulted in a distinct pattern in the hepatic BA synthesis between the NM and LM groups. NM mice exhibited a lowered BA synthetic level (a reduced Cyp7a1 expression with decrease of free BAs in liver and serum), which is in line with the activated intestinal feedback control signaling.…”

Section: Discussioncontrasting

confidence: 99%

A High Hepatic Uptake of Conjugated Bile Acids Promotes Colorectal Cancer—Associated Liver Metastasis

Zheng

Wei

Hou

et al. 2022

Cells

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The liver is the most common site for colorectal cancer (CRC)–associated metastasis. There remain unsatisfactory medications in liver metastasis given the incomplete understanding of pathogenic mechanisms. Herein, with an orthotopic implantation model fed either regular or high-fat diets (HFD), more liver metastases were associated with an expansion of conjugated bile acids (BAs), particularly taurocholic acid (TCA) in the liver, and an increased gene expression of Na+–taurocholate cotransporting polypeptide (NTCP). Such hepatic BA change was more apparently shown in the HFD group. In the same model, TCA was proven to promote liver metastases and induce a tumor-favorable microenvironment in the liver, characterizing a high level of fibroblast activation and increased proportions of myeloid-derived immune cells. Hepatic stellate cells, a liver-residing source of fibroblasts, were dose-dependently activated by TCA, and their conditioned medium significantly enhanced the migration capability of CRC cells. Blocking hepatic BA uptake with NTCP neutralized antibody can effectively repress TCA–triggered liver metastases, with an evident suppression of tumor microenvironment niche formation. This study points to a new BA–driven mechanism of CRC–associated liver metastases, suggesting that a reduction of TCA overexposure by limiting liver uptake is a potential therapeutic option for CRC—associated liver metastasis.

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Section: Discussioncontrasting

confidence: 99%

A High Hepatic Uptake of Conjugated Bile Acids Promotes Colorectal Cancer—Associated Liver Metastasis

Zheng

Wei

Hou

et al. 2022

Cells

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“…Increased levels of cholesterol 25-hydroxylase (Ch25 h) and its enzymatic by-product 25HC in the liver prevent high-fat diet-induced hepatic steatosis. This beneficial mechanism involves the regulation of enterohepatic circulation of bile acids by the induction of the CYP7A1 gene via activation of LXR-α (Dong et al, 2022). Our data show that withaferin A also activates LXR-α and similarly induces its canonical target genes to that of 25HC and mimics and exerts similar effects on NAFLD.…”

Section: Discussionmentioning

confidence: 60%

The ameliorating effect of withaferin A on high-fat diet-induced non-alcoholic fatty liver disease by acting as an LXR/FXR dual receptor activator

Shiragannavar

Gowda

Puttahanumantharayappa

et al. 2023

Front. Pharmacol.

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Introduction: Non-alcoholic fatty liver disease (NAFLD) incidence has been rapidly increasing, and it has emerged as one of the major diseases of the modern world. NAFLD constitutes a simple fatty liver to chronic non-alcoholic steatohepatitis (NASH), which often leads to liver fibrosis or cirrhosis, a serious health condition with limited treatment options. Many a time, NAFLD progresses to fatal hepatocellular carcinoma (HCC). Nuclear receptors (NRs), such as liver X receptor-α (LXR-α) and closely associated farnesoid X receptor (FXR), are ligand-inducible transcription factors that regulate various metabolism-associated gene expressions and repression and play a major role in controlling the pathophysiology of the human liver. Withaferin A is a multifaceted and potent natural dietary compound with huge beneficial properties and plays a vital role as an anti-inflammatory molecule.Methods:In vivo: Swill albino mice were fed with western diet and sugar water (WDSW) for 12, 16, and 20 weeks with suitable controls. Post necropsy, liver enzymes (AST, ALT, and ALP) and lipid profile were measured by commercially available kits using a semi-auto analyzer in serum samples. Liver histology was assessed using H&E and MTS stains to check the inflammation and fibrosis, respectively, using paraffin-embedded sections and mRNA expressions of these markers were measured using qRT-PCR method. TGF-β1 levels in serum samples were quantified by ELISA. In vitro: Steatosis was induced in HepG2 and Huh7 cells using free fatty acids [Sodium Palmitate (SP) and Oleate (OA)]. After induction, the cells were treated with Withaferin A in dose-dependent manner (1, 2.5, and 5 μM, respectively). In vitro steatosis was confirmed by Oil-Red-O staining. Molecular Docking: Studies were conducted using Auto Dock Vina software to check the binding affinity of Withaferin-A to LXR-α and FXR.Results: We explored the dual receptor-activating nature of Withaferin A using docking studies, which potently improves high-fat diet-induced NAFLD in mice and suppresses diet-induced hepatic inflammation and liver fibrosis via LXR/FXR. Our in vitro studies also indicated that Withaferin A inhibits lipid droplet accumulation in sodium palmitate and oleate-treated HepG2 and Huh7 cells, which may occur through LXR-α and FXR-mediated signaling pathways. Withaferin A is a known inhibitor of NF-κB-mediated inflammation. Intriguingly, both LXR-α and FXR activation inhibits inflammation and fibrosis by negatively regulating NF-κB. Additionally, Withaferin A treatment significantly inhibited TGF-β-induced gene expression, which contributes to reduced hepatic fibrosis.Discussion: Thus, the LXR/ FXR dual receptor activator Withaferin A improves both NAFLD-associated liver inflammation and fibrosis in mouse models and under in vitro conditions, which makes Withaferin A a possibly potent pharmacological and therapeutic agent for the treatment of diet-induced NAFLD.

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“…Real-time PCR was performed with a total volume of 20 μl, which contained 2 μl of cDNA, 0.4 μl of each 10 μM forward and reverse primer, 5.2 ml of ddH2O and 10 μl of 2×PerfectStart® Green qPCR SuperMix (TransGen Biotech) on a CFX96 TM Real-Time PCR Detection System. PCR amplification was performed using cycling conditions of 94°C for 30 s, followed by 45 cycles of 94°C for 5 s and 60°C for 30 s. Relative gene expression changes were measured by the comparative Ct method, X = 2 -△△Ct ( Dong et al, 2022 ), using GAPDH as our housekeeping internal control gene. The primers used for qPCR are listed in Supplementary Table S3 .…”

Section: Methodsmentioning

confidence: 99%

Novel active compounds and the anti-diabetic mechanism of mulberry leaves

Lin

et al. 2022

Front. Pharmacol.

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Mulberry (Morus alba L.) leaves have long been considered beneficial in traditional Chinese medicine to treat infectious and internal diseases. Recently studies have discovered that the mulberry leaf’s total flavonoids (MLF) display excellent hypoglycemia properties. However, the active ingredients and their molecular mechanisms are still uncharacterized. In this study, we explored the hypoglycemic effects of MLF and mulberry leaf polysaccharides (MLP) on ob/ob mice, an animal model of type 2 diabetes mellitus (T2DM), compared with Ramulus Mori (Sangzhi) alkaloid (RMA). Network pharmacology was employed to identify the potential available targets and active compounds of MLF and RMA against hyperglycemia. Molecular docking, an insulin-resistant cell model and qPCR were employed to verify the antidiabetic activity of the critical compounds and the gene expression profiles of the top molecular targets. Here, the results showed that MLF and MLP improved glucose uptake in insulin-resistant hepatocytes. MLF, MLP and RMA alleviated insulin resistance and glucose intolerance in ob/ob mice. Unlike MLF and MLP, RMA administration did not influence the accumulation of intrahepatic lipids. Network pharmacology analysis revealed that morusin, kuwanon C and morusyunnansin L are the main active compounds of MLF and that they amend insulin resistance and glycemia via the PI3K- Akt signaling pathway, lipid and atherosclerosis pathways, and the AGE-RAGE signaling pathway. Moreover, 1-deoxynojirimycin (DNJ), fagomine (FA), and N-methyl-1-deoxynojirimycin are the primary active ingredients of RMA and target carbohydrate metabolism and regulate alpha-glucosidase activity to produce a potent anti-diabetic effect. The molecular docking results indicated that morusin, kuwanon C and morusyunnansin L are the critical bioactive compounds of MLF. They had high affinities with the key targets adenosine A1 receptor (ADORA1), AKT serine/threonine kinase 1 (AKT1), peroxisome proliferator-activated receptor gamma (PPARγ), and glycogen synthase kinase 3 beta (GSK3β), which play crucial roles in the MLF-mediated glucose-lowering effect. Additionally, morusin plays a role in amending insulin resistance of hepatocytes by repressing the expression of the ADORA1 and PPARG genes. Our results shed light on the mechanism behind the glucose-lowering effects of MLF, suggesting that morusin, kuwanon C, and morusyunnansin L might be promising drug leads for the management of T2DM.

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Hepatic Reduction in Cholesterol 25-Hydroxylase Aggravates Diet-induced Steatosis

Cited by 13 publications

References 43 publications

A High Hepatic Uptake of Conjugated Bile Acids Promotes Colorectal Cancer—Associated Liver Metastasis

A High Hepatic Uptake of Conjugated Bile Acids Promotes Colorectal Cancer—Associated Liver Metastasis

The ameliorating effect of withaferin A on high-fat diet-induced non-alcoholic fatty liver disease by acting as an LXR/FXR dual receptor activator

Novel active compounds and the anti-diabetic mechanism of mulberry leaves

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