steatosis

LI-2242 is a potent inositol hexakisphosphate kinase (IP6K) inhibitor with IC50s of 31 nM, 42 nM, 8.7 nM, and 1944 nM for IP6K1, IP6K2, IP6K3, and IPMK, respectively.LI-2242 ameliorated hepatic steatosis by reducing the expression of genes that enhance lipid uptake, lipid stabilization, and adipogenesis, and enhanced mitochondrial oxygen consumption rate (OCR) and insulin signaling in adipocytes and hepatocytes in vitro. LI-2242 ameliorated diet-induced obesity, hyperglycemia and hepatic steatosis in mice.LI-2242 can be used to study type II diabetes, obesity, metabolic complications, venous thrombosis and psychiatric disorders.

Obeticholic Acid (6-ECDCA, INT-747) is a high-affinity, semisynthetic, bile acid-derived FXR agonist with an EC50 of 99 nM and is able to upregulate IκB-α, KLF-2, and KLF-4 expression. Obeticholic Acid (6-ECDCA, INT-747) also shows potential for treating hepatic steatosis, inflammation, and fibrosis while increasing insulin sensitivity.

Orotic acid zinc (Zinc Orotate) salt dihydrate is an intermediate product in pyrimidine synthesis.

Orotic acid (Vitamin B13) is an intermediate product in pyrimidine metabolism.

MK-0626 is an orally available dipeptidyl peptidase IV (DPP-4) inhibitor that attenuates hepatic steatosis and accumulation by enhancing AMPK activity.MK-0626 attenuates TAC-induced diabetic pancreatic islet injury by restoring the expression of GLP-1R.MK-0626 is able to increase circulating endothelial progenitor cell numbers and endothelial-type nitric oxide synthase expression by promoting neoangiogenesis.

L-Chicoric Acid (trans-Caffeoyltartaric acid) has been shown to inhibit hyaluronidase and HIV-1 integrase, and to possess phagoeytosis stimulatory activity in vitro and in vivo and antiviral acitivy. L-Chicoric acid may reduce acute alcohol-induced steatosis in mice through interfering with the induction of iNOS and iNOS-dependent signaling cascades in the liver. 3. L-Chicoric acid inhibited cell viability and induced apoptosis in 3T3-L1 preadipocytes which was characterized by chromatin condensation and poly ADP-ribose-polymerase (PARP) cleavage.

1. Eriocitrin (Eriodictyol-7-O-Rutinoside) is powerful antioxidative flavonoid; (1) Prevents oxidative damages caused by acute exercise-induced oxidative stress.(2) Lipid-lowering effects in a rat model of high-fat diet. 2. Dietary Eriocitrin ameliorates diet-induced hepatic steatosis with activation of mitochondrial biogenesis. 3. Eriocitrin and Apigenin were identified as new potent inhibitors of human carbonic anhydrase VA isozyme.

Scopolin (Scopoloside) formation is increased by the enhanced activity of PAL. Scopolin can reduce the clinical symptoms of rat AIA by inhibiting inflammation and angiogenesis, and this compound may be a potent agent for angiogenesis related diseases and can serve as a structural base for screening more potent synthetic analogs.

SBI993 is an analog of SBI-477 and can be used as a biomarker to confirm the expected action of MondoA target gene expression in vivo. SBI993 reduces muscle TAG levels and hepatic steatosis.

4-Hydroxyflavanone is a natural product, shows full vasorelaxing effects

1-Pentadecanoyl-rac-glycerol is a monoacylglycerol that contains pentadecanoic acid at the sn-1 position. It has been found in wheat bran extracts.1 1-Pentadecanoyl-rac-glycerol levels are increased in a HepaRG cell-based model of hepatic steatosis induced by BSA-conjugated palmitate.2 |1. Prinsen, P., Gutiérrez, A., Faulds, C.B., et al. Comprehensive study of valuable lipophilic phytochemicals in wheat bran. J. Agric. Food Chem. 62(7), 1664-1673 (2014).|2. Brown, M.V., Compton, S.A., Milburn, M.V., et al. Metabolomic signatures in lipid-loaded HepaRGs reveal pathways involved in steatotic progression. Obesity (Silver Spring) 21(12), E561-E570 (2013).

Tripalmitolein is a triacylglycerol that contains palmitoleic acid at the sn-1, sn-2, and sn-3 positions. It reduces red blood cell deformability in a concentration-dependent manner in a Reid's filtration assay. Hepatic levels of 1,2,3-tripalmitoleoyl-rac-glycerol are increased in the JAK2L mouse model of hepatic steatosis. Tripalmitolein plasma levels are decreased in renal patients before dialysis.

Calcium palmitate, a long-chain saturated fatty acid prevalent in animals and plants, induces the expression of glucose-regulated protein 78 (GRP78) and CCAAT/enhancer binding protein homologous protein (CHOP) in mouse granulosa cells. It is employed to establish a cell steatosis model [1] [2].

ZLY032 is a dual agonist of free fatty acid receptor 1 (FFAR1/GPR40; EC50= 68 nM in a FLIPR assay) and peroxisome proliferator-activated receptor δ (PPARδ; EC50= 102 nM in a reporter assay).1It is selective for FFAR1 and PPARδ over PPARα and PPARγ (EC50s = >10 μM for both). ZLY032 (40 mg/kg, twice per day) reduces blood glucose levels in an oral glucose tolerance test and decreases plasma total cholesterol and triglyceride levels in theob/obmouse model of metabolic disease.2It reduces hepatic steatosis and plasma alanine transaminase (ALT) and aspartate aminotransferase (AST) levels in a mouse model of non-alcoholic steatohepatitis (NASH) induced by a methionine and choline-deficient diet at the same dose. 1.Li, Z., Chen, Y., Zhou, Z., et al.Discovery of first-in-class thiazole-based dual FFA1/PPARδ agonists as potential anti-diabetic agentsEur. J. Med. Chem.164352-365(2019) 2.Li, Z., Zhou, Z., Hu, L., et al.ZLY032, the first-in-class dual FFA1/PPARδ agonist, improves glucolipid metabolism and alleviates hepatic fibrosisPharmacol Res.159105035(2020)

Ajoene is a disulfide that has been found inA. sativumand has diverse biological activities, including antibacterial, anticancer, antiplatelet, and antioxidant properties.1,2,3,4It is active against Gram-positive (MICs = 5-160 µg/ml) and Gram-negative bacteria (MICs = 136-200 µg/ml), as well as yeasts (MICs = 10-20 µg/ml).1Ajoene is cytotoxic to mouse melanoma cells (IC50= 18 µM), as well as human colon, lung, mammary, and pancreatic cancer cells (IC50s = 7-41 µM).2It reduces tumor growth in a B16/BL6 mouse model of melanoma when administered at a dose of 25 mg/kg every other day and decreases the number of lung metastases when administered prior to tumor cell inoculation at doses ranging from 1-25 mg/kg. It inhibits ADP- or collagen-induced platelet aggregation in isolated baboon platelets when used at concentrations ranging from 75 to 150 µg/ml and in platelet-rich plasma isolated from baboons when administered at a dose of 25 mg/kg.3Ajoene (25 mg/kg) prevents thrombus formation on damaged arterial walls in heparinized pigs in anin situmodel of thrombogenesis.5It also reduces high-fat diet-induced hepatic steatosis, histopathological markers of liver damage, thiobarbituric acid reactive substances (TBARS) formation, and protein oxidation in a mouse model of non-alcoholic fatty liver disease (NAFLD).4 1.Naganawa, R., Iwata, N., Ishikawa, K., et al.Inhibition of microbial growth by ajoene, a sulfur-containing compound derived from garlicAppl. Environ. Microbiol.62(11)4238-4242(1996) 2.Taylor, P., Noriega, R., Farah, C., et al.Ajoene inhibits both primary tumor growth and metastasis of B16/BL6 melanoma cells in C57BL/6 miceCancer Lett.239(2)298-304(2006) 3.Teranishi, K., Apitz-Castro, R., Robson, S.C., et al.Inhibition of baboon platelet aggregation in vitro and in vivo by the garlic derivative, ajoeneXenotransplantation10(4)374-379(2003) 4.Han, C.Y., Ki, S.H., Kim, Y.W., et al.Ajoene, a stable garlic by-product, inhibits high fat diet-induced hepatic steatosis and oxidative injury through LKB1-dependent AMPK activationAntioxid. Redox Signal.14(2)187-202(2011) 5.Apitz-Castro, R., Badimon, J.J., and Badimon, L.A garlic derivative, ajoene, inhibits platelet deposition on severely damaged vessel wall in an in vivo porcine experimental modelThromb. Res.75(3)243-249(1994)

Ervogastat (PF-06865571) is a potent and well-tolerated diacylglycerol acyltransferase 2 inhibitor. Ervogastat reduces steatosis and hepatic triglyceride levels in non-alcoholic steatohepatitis (NASH).

SRI-37330 inhibits glucagon secretion and function, reduces hepatic glucose production, and reverses hepatic steatosis.

FXR antagonist 1 is a selective, orally active intestinal FXR antagonist with an IC50 value of 2.1 μM. FXR antagonist 1 antagonises intestinal FXR and selectively inhibits intestinal FXR signalling by feedback activation of hepatic FXR. FXR antagonist 1 can improve liver steatosis, inflammation and fibrosis in the NASH (non-alcoholic steatohepatitis) model and can be used to study NASH.

SET-171 is a JNK (c-Jun N-terminal kinase) inhibitor that exhibits significant anticancer activity by suppressing the expression of hepatic pyruvate kinase (PKL) and offers potential in regulating lipid metabolism. In antitumor studies, SET-171 shows notable cytotoxicity against human liver cancer cell lines HepG2 and Huh7, with IC50 values of 8.82 μM and 2.97 μM, respectively. Additionally, in research related to non-alcoholic fatty liver disease (NAFLD), SET-171 significantly reduces triglyceride (TAG) levels and inhibits the expression of proteins associated with steatosis. This compound holds promise for hepatocellular carcinoma (HCC) and NAFLD research.

CTPI-2 is an inhibitor of mitochondrial citrate carrier SLC25A1 with(KD : 3.5 μM). CTPI-2 inhibits glycolysis, PPARγ, and its downstream target the glucose transporter GLUT4. CTPI-2 exhibits anti-tumor activity.CTPI-2 halts salient alterations of NASH reverting steatosis, preventing the evolution to steatohepatitis, reducing inflammatory macrophage infiltration in the liver and adipose tissue, and starkly mitigating obesity induced by a high-fat diet.

1. Rhapontin (Ponticin) can alleviate liver steatosis and improve blood glucose and lipid profiles in KK Ay diabetic mice, indicates that rhaponticin has a noticeable antidiabetic effect and could be potentially used as a new agent to treat type 2 diabetes mellitus and its complications.

Anti-NASH agent 2 (compound 21) is an inhibitor of neolipogenesis activity and α-SMA gene expression. It improves hepatic steatosis, edema, inflammatory infiltration, and liver fibrosis in NASH mouse models.

Mannan is isolated from algae, mushrooms, yeast and higher plants and acts as an immunomodulator.Mannan inhibits the pro-inflammatory activity of hepatic macrophages (M1 lineage) with protective effects against many liver lesions such as necrosis or steatosis.

SHS4121705 is an orally bioavailable mitochondrial uncoupler.1It increases oxygen consumption rate in L6 rat myoblast cells with an EC50value of 4.3 μM. SHS4121705 (25 mg/kg per day in the diet) reduces hepatic steatosis, liver triglyceride levels, and plasma alanine aminotransferase (ALT) levels in Stelic animal model (STAM) mice, a model of non-alcoholic steatohepatitis (NASH). 1.Salamoun, J.M., Garcia, C.J., Hargett, S.R., et al.6-Amino[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol derivatives as efficacious mitochondrial uncouplers in STAM mouse model of nonalcoholic steatohepatitisJ. Med. Chem.63(11)6203-6224(2020)