Monoacylglycerol Acyltransferase 2 (MGAT2) Inhibitors for the Treatment of Metabolic Diseases and Nonalcoholic Steatohepatitis (NASH)

2018 ◽  
Vol 61 (22) ◽  
pp. 9879-9888 ◽  
Author(s):  
Pratik Devasthale ◽  
Dong Cheng
Keyword(s):  
Nonalcoholic Steatohepatitis ◽  
Metabolic Diseases ◽  
Monoacylglycerol Acyltransferase

scholarly journals Berberine Prevents Disease Progression of Nonalcoholic Steatohepatitis through Modulating Multiple Pathways

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 210
Author(s):  
Yanyan Wang ◽  
Yun-Ling Tai ◽  
Derrick Zhao ◽  
Yuan Zhang ◽  
Junkai Yan ◽  
...  
Keyword(s):  
Bile Acid ◽  
Mouse Model ◽  
Disease Progression ◽  
Nonalcoholic Steatohepatitis ◽  
Noncoding Rna ◽  
Metabolic Diseases ◽  
Immune Cell ◽  
Stellate Cell ◽  
Clinical Investigation ◽  
Beneficial Effects

Background and Aims: The disease progression of nonalcoholic fatty liver disease (NAFLD) from simple steatosis (NAFL) to nonalcoholic steatohepatitis (NASH) is driven by multiple factors. Berberine (BBR) is an ancient Chinese medicine and has various beneficial effects on metabolic diseases, including NAFLD/NASH. However, the underlying mechanisms remain incompletely understood due to the limitation of the NASH animal models used. Methods: A high-fat and high-fructose diet-induced mouse model of NAFLD, the best available preclinical NASH mouse model, was used. RNAseq, histological, and metabolic pathway analyses were used to identify the potential signaling pathways modulated by BBR. LC–MS was used to measure bile acid levels in the serum and liver. The real-time RT-PCR and Western blot analysis were used to validate the RNAseq data. Results: BBR not only significantly reduced hepatic lipid accumulation by modulating fatty acid synthesis and metabolism but also restored the bile acid homeostasis by targeting multiple pathways. In addition, BBR markedly inhibited inflammation by reducing immune cell infiltration and inhibition of neutrophil activation and inflammatory gene expression. Furthermore, BBR was able to inhibit hepatic fibrosis by modulating the expression of multiple genes involved in hepatic stellate cell activation and cholangiocyte proliferation. Consistent with our previous findings, BBR’s beneficial effects are linked with the downregulation of microRNA34a and long noncoding RNA H19, which are two important players in promoting NASH progression and liver fibrosis. Conclusion: BBR is a promising therapeutic agent for NASH by targeting multiple pathways. These results provide a strong foundation for a future clinical investigation.

scholarly journals Efficacy and Mechanism of a Chinese Classic Prescription of Yueju in Treating Nonalcoholic Steatohepatitis and Protecting Hepatocytes from Apoptosis

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Xiao-Li He ◽  
Yan-Ming He ◽  
Dan Zhang ◽  
Hong-Shan Li ◽  
Qiang Zhang ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Nonalcoholic Steatohepatitis ◽  
Fatty Acid Synthase ◽  
Metabolic Diseases ◽  
Smooth Muscle Actin ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
High Cholesterol Diet ◽  
Apoptosis Protein ◽  
Abnormal Lipid Metabolism

Yueju, a famous classic Chinese prescription, has been extensively used in treating depression syndromes for hundreds of years. Recent studies have reported that Yueju showed good effects in treating metabolic diseases, such as obesity and hyperlipidemia. Nonalcoholic steatohepatitis (NASH), which leads to cirrhosis and severe cardiovascular diseases, is closely linked to obesity and abnormal lipid metabolism. In this study, Yueju could decrease the levels of alanine aminotransferase, aspartate transaminase, triglyceride, cholesterol, and low-density lipoprotein-C but increase the high-density lipoprotein-C in the serum of the NASH rat model induced by high-fat and high-cholesterol diet. Yueju could alleviate hepatosteatosis by increasing the phosphorylation of acetyl-CoA carboxylase and inhibiting the expression of fatty acid synthase and stearoyl-CoA desaturase 1. Yueju downregulated the expression of α-smooth muscle actin and collagen type 1A1, ameliorating the liver fibrilization. Yueju could also protect the hepatocytes from apoptosis by upregulating antiapoptosis protein Bcl-2 and X-linked inhibitor of apoptosis protein and downregulating apoptotic proteins Bax and cleaved poly ADP-ribose polymerase. Thus, Yueju could improve liver function, regulate lipid metabolism, alleviate hepatosteatosis and fibrosis, and protect hepatocytes from apoptosis against NASH. Yueju may be used as an alternative effective medicine for NASH treatment.

scholarly journals Novel LC/MS/MS and High-Throughput Mass Spectrometric Assays for Monoacylglycerol Acyltransferase Inhibitors

2017 ◽  
Vol 22 (4) ◽  
pp. 433-439
Author(s):  
Jenson Qi ◽  
John A. Masucci ◽  
Wensheng Lang ◽  
Margery A. Connelly ◽  
Gary W. Caldwell ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
High Throughput ◽  
Metabolic Diseases ◽  
Host Cells ◽  
Activity Assay ◽  
Highly Sensitive ◽  
Liquid Chromatography Tandem Mass ◽  
Acyltransferase Inhibitors ◽  
Tlc Analysis ◽  
Monoacylglycerol Acyltransferase

Monoacylglycerol acyltransferase enzymes (MGAT1, MGAT2, and MGAT3) convert monoacylglycerol to diacylglycerol (DAG). MGAT1 and MGAT2 are both implicated in obesity-related metabolic diseases. Conventional MGAT enzyme assays use radioactive substrates, wherein the product of the MGAT-catalyzed reaction is usually resolved by time-consuming thin layer chromatography (TLC) analysis. Furthermore, microsomal membrane preparations typically contain endogenous diacylglycerol acyltransferase (DGAT) from the host cells, and these DGAT activities can further acylate DAG to form triglyceride (TG). Our mass spectrometry (liquid chromatography–tandem mass spectrometry, or LC/MS/MS) MGAT2 assay measures human recombinant MGAT2-catalyzed formation of didecanoyl-glycerol from 1-decanoyl-rac-glycerol and decanoyl-CoA, to produce predominantly 1,3-didecanoyl-glycerol. Unlike 1,2-DAG, 1,3-didecanoyl-glycerol is proved to be not susceptible to further acylation to TG. 1,3-Didecanoyl-glycerol product can be readily solubilized and directly subjected to high-throughput mass spectrometry (HTMS) without further extraction in a 384-well format. We also have established the LC/MS/MS MGAT activity assay in the intestinal microsomes from various species. Our assay is proved to be highly sensitive, and thus it allows measurement of endogenous MGAT activity in cell lysates and tissue preparations. The implementation of the HTMS MGAT activity assay has facilitated the robust screening and evaluation of MGAT inhibitors for the treatment of metabolic diseases.

scholarly journals Peculiarities of Cirrhosis due to Nonalcoholic Steatohepatitis (NASH)

2019 ◽  
Vol 40 (01) ◽  
pp. 001-010
Author(s):  
Omar El-Sherif ◽  
M.J. Armstrong
Keyword(s):  
Hepatocellular Carcinoma ◽  
Nonalcoholic Steatohepatitis ◽  
Metabolic Diseases ◽  
Nutritional Assessment ◽  
The United States ◽  
Obesity And Diabetes ◽  
Noninvasive Assessment ◽  
New Challenges ◽  
Complications Of Cirrhosis ◽  
The Impact

AbstractThe prevalence of cirrhosis due to nonalcoholic steatohepatitis (NASH) has increased 2.5-fold in the United States in the last decade. These patients pose new challenges to hepatologists given their older age and higher frequency of coexisting metabolic diseases such as obesity and diabetes compared with other etiologies of liver disease. Patients with NASH cirrhosis are at higher risk for renal and cardiovascular disease, and the presence of these extrahepatic comorbidities has a significant impact on outcomes and survival. This review outlines how NASH cirrhosis differs from other etiologies of cirrhosis including natural history, noninvasive assessment, and the challenges in the management of the complications of cirrhosis including hepatic encephalopathy and hepatocellular carcinoma. Nutritional assessment and the impact of sarcopenic obesity and frailty in this population, and strategies to address the latter, are discussed. This review also addresses liver transplantation in patients with NASH cirrhosis in relation to assessment and posttransplant care.

scholarly journals Nonalcoholic steatohepatitis is frequently accompanied by metabolic diseases

Hepatology ◽  
2008 ◽  
Vol 48 (5) ◽  
pp. 1728-1728 ◽  
Author(s):  
Teoman Dogru ◽  
Cemal Nuri Ercin ◽  
Gokhan Erdem ◽  
Ilker Tasci ◽  
Alper Sonmez ◽  
...  
Keyword(s):  
Nonalcoholic Steatohepatitis ◽  
Metabolic Diseases

scholarly journals Salidroside Modulates Insulin Signaling in a Rat Model of Nonalcoholic Steatohepatitis

2017 ◽  
Vol 2017 ◽  
pp. 1-6 ◽  
Author(s):  
Hongshan Li ◽  
Hao Ying ◽  
Airong Hu ◽  
Dezhou Li ◽  
Yaoren Hu
Keyword(s):  
Signaling Pathway ◽  
Rat Model ◽  
Insulin Signaling ◽  
Nonalcoholic Steatohepatitis ◽  
High Fat Diet ◽  
Metabolic Diseases ◽  
Insulin Signaling Pathway ◽  
Hepatic Tissue ◽  
Therapeutic Effects ◽  
High Fat

A growing body of evidence has shown the beneficial effects of salidroside in cardiovascular and metabolic diseases. This study aimed to evaluate the therapeutic effects of salidroside on nonalcoholic steatohepatitis (NASH) in rats and explore the underlying mechanisms related to insulin signaling. A rat model of NASH was developed by high-fat diet for 14 weeks. From week 9 onward, the treatment group received oral salidroside (4.33 mg/kg) daily for 6 weeks. Salidroside effectively attenuated steatosis and vacuolation of hepatic tissue, with a dramatic decrease in liver triglycerides and free fatty acid levels (P < 0.01). Dysregulation of FINS, FBG, HOMA-IR, ALT, and AST in serum was ameliorated with salidroside treatment (P < 0.01). In the liver, salidroside induced significant increases in key molecules in the insulin signaling pathway, such as phosphorylated insulin receptor substrate 1 (IRS1), phosphoinositide 3-kinase (PI3K), and protein kinase B (PKB), with a significant decrease in SREBP-1c levels (P < 0.01). Therefore, salidroside effectively protected rats from high-fat-diet-induced NASH, which may be partially attributed to its effects on the hepatic insulin signaling pathway.

scholarly journals The effects of B1344, a novel fibroblast growth factor 21 analog, on nonalcoholic steatohepatitis in nonhuman primates

2020 ◽  
Author(s):  
Ada Admin ◽  
Aoyuan Cui ◽  
Jian Li ◽  
Shaohui Ji ◽  
Fengguang Ma ◽  
...  
Keyword(s):  
Liver Biopsy ◽  
Nonalcoholic Steatohepatitis ◽  
Metabolic Diseases ◽  
Primate Species ◽  
Fibroblast Growth Factor 21 ◽  
Dependent Manner ◽  
Nonalcoholic Fatty Liver ◽  
Long Acting ◽  
Hepatocyte Death

Nonalcoholic steatohepatitis has emerged as a major cause of liver diseases with no effective therapies. Here, we evaluate the efficacies and pharmacokinetics of B1344, a long-acting PEGylated FGF21 analog, in a nongenetically modified nonhuman primate species that underwent liver biopsy, and demonstrate the potential for efficacies in humans. B1344 is sufficient to selectively activate signaling from the βKlotho/FGFR1c receptor complex. In cynomolgus monkeys with nonalcoholic fatty liver disease, administration of B1344 via subcutaneous injection for eleven weeks caused a profound reduction of hepatic steatosis, inflammation and fibrosis, and amelioration of liver injury and hepatocyte death as evidenced by liver biopsy and biochemical analysis. Moreover, improvement of metabolic parameters was observed in the monkey, including reduction of body weight and improvement of lipid profiles and glycemic control. To determine the role of B1344 in the progression of murine NAFLD independent of obesity, administration of B1344 were performed in mice fed with methionine and choline deficiency diet. Consistently, B1344 administration prevented the mice from lipotoxicity damage and nonalcoholic steatohepatitis at a dose-dependent manner. These results provide preclinical validation for an innovative therapeutics to NAFLD, and support further clinical testing of B1344 for treating nonalcoholic steatohepatitis and other metabolic diseases in humans.

scholarly journals Advances and challenges in the management of advanced fibrosis in nonalcoholic steatohepatitis

2018 ◽  
Vol 11 ◽  
pp. 175628481881150 ◽  
Author(s):  
Mehmet Sayiner ◽  
Brian Lam ◽  
Pegah Golabi ◽  
Zobair M. Younossi
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Disease ◽  
Nonalcoholic Steatohepatitis ◽  
Metabolic Diseases ◽  
Lifestyle Modification ◽  
Visceral Obesity ◽  
Nonalcoholic Fatty Liver ◽  
Risk Of Mortality ◽  
Increased Risk ◽  
Risk Of Progression

Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming the most common type of chronic liver disease worldwide. From the spectrum of NAFLD, it is nonalcoholic steatohepatitis (NASH) that predominantly predisposes patients to higher risk for development of cirrhosis and hepatocellular carcinoma. There is growing evidence that the risk of progression to cirrhosis and hepatocellular carcinoma is not uniform among all patients with NASH. In fact, NASH patients with increasing numbers of metabolic diseases such as diabetes, hypertension, visceral obesity and dyslipidemia are at a higher risk of mortality. Additionally, patients with higher stage of liver fibrosis are also at increased risk of mortality. In this context, NASH patients with fibrosis are in the most urgent need of treatment. Also, the first line of treatment for NASH is lifestyle modification with diet and exercise. Nevertheless, the efficacy of lifestyle modification is quite limited. Additionally, vitamin E and pioglitazone may be considered for subset of patients with NASH. There are various medications targeting one or more steps in the pathogenesis of NASH being developed. These drug regimens either alone or in combination, may provide potential treatment option for patients with NASH.

scholarly journals The effects of B1344, a novel fibroblast growth factor 21 analog, on nonalcoholic steatohepatitis in nonhuman primates

2020 ◽  
Author(s):  
Ada Admin ◽  
Aoyuan Cui ◽  
Jian Li ◽  
Shaohui Ji ◽  
Fengguang Ma ◽  
...  
Keyword(s):  
Liver Biopsy ◽  
Nonalcoholic Steatohepatitis ◽  
Metabolic Diseases ◽  
Primate Species ◽  
Fibroblast Growth Factor 21 ◽  
Dependent Manner ◽  
Nonalcoholic Fatty Liver ◽  
Long Acting ◽  
Hepatocyte Death

Nonalcoholic steatohepatitis has emerged as a major cause of liver diseases with no effective therapies. Here, we evaluate the efficacies and pharmacokinetics of B1344, a long-acting PEGylated FGF21 analog, in a nongenetically modified nonhuman primate species that underwent liver biopsy, and demonstrate the potential for efficacies in humans. B1344 is sufficient to selectively activate signaling from the βKlotho/FGFR1c receptor complex. In cynomolgus monkeys with nonalcoholic fatty liver disease, administration of B1344 via subcutaneous injection for eleven weeks caused a profound reduction of hepatic steatosis, inflammation and fibrosis, and amelioration of liver injury and hepatocyte death as evidenced by liver biopsy and biochemical analysis. Moreover, improvement of metabolic parameters was observed in the monkey, including reduction of body weight and improvement of lipid profiles and glycemic control. To determine the role of B1344 in the progression of murine NAFLD independent of obesity, administration of B1344 were performed in mice fed with methionine and choline deficiency diet. Consistently, B1344 administration prevented the mice from lipotoxicity damage and nonalcoholic steatohepatitis at a dose-dependent manner. These results provide preclinical validation for an innovative therapeutics to NAFLD, and support further clinical testing of B1344 for treating nonalcoholic steatohepatitis and other metabolic diseases in humans.

scholarly journals The effects of B1344, a novel fibroblast growth factor 21 analog, on nonalcoholic steatohepatitis in nonhuman primates

2020 ◽  
Author(s):  
Ada Admin ◽  
Aoyuan Cui ◽  
Jian Li ◽  
Shaohui Ji ◽  
Fengguang Ma ◽  
...  
Keyword(s):  
Liver Biopsy ◽  
Nonalcoholic Steatohepatitis ◽  
Metabolic Diseases ◽  
Primate Species ◽  
Fibroblast Growth Factor 21 ◽  
Dependent Manner ◽  
Nonalcoholic Fatty Liver ◽  
Long Acting ◽  
Hepatocyte Death

Nonalcoholic steatohepatitis has emerged as a major cause of liver diseases with no effective therapies. Here, we evaluate the efficacies and pharmacokinetics of B1344, a long-acting PEGylated FGF21 analog, in a nongenetically modified nonhuman primate species that underwent liver biopsy, and demonstrate the potential for efficacies in humans. B1344 is sufficient to selectively activate signaling from the βKlotho/FGFR1c receptor complex. In cynomolgus monkeys with nonalcoholic fatty liver disease, administration of B1344 via subcutaneous injection for eleven weeks caused a profound reduction of hepatic steatosis, inflammation and fibrosis, and amelioration of liver injury and hepatocyte death as evidenced by liver biopsy and biochemical analysis. Moreover, improvement of metabolic parameters was observed in the monkey, including reduction of body weight and improvement of lipid profiles and glycemic control. To determine the role of B1344 in the progression of murine NAFLD independent of obesity, administration of B1344 were performed in mice fed with methionine and choline deficiency diet. Consistently, B1344 administration prevented the mice from lipotoxicity damage and nonalcoholic steatohepatitis at a dose-dependent manner. These results provide preclinical validation for an innovative therapeutics to NAFLD, and support further clinical testing of B1344 for treating nonalcoholic steatohepatitis and other metabolic diseases in humans.

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