This study will evaluate changes in liver fat content following multiple oral doses of MK-4074 and Pioglitazone Hydrochloride in adult males and females with fatty liver disease. The primary hypothesis of the study is that a multiple-dose administration of MK-4074 200 mg twice daily for 4 weeks results in a decrease in hepatic fat content with respect to placebo in adult male and female participants with hepatic steatosis (i.e., on order of 50% reduction in hepatic fat with respect to placebo is expected).

Start Date26 Oct 2011

Sponsor / Collaborator

Merck Sharp & Dohme Corp.

100 Clinical Results associated with MK-4074

100 Translational Medicine associated with MK-4074

100 Patents (Medical) associated with MK-4074

Literatures (Medical) associated with MK-4074

07 Jul 2022·World Journal of Gastroenterology

Mechanism and therapeutic strategy of hepatic TM6SF2-deficient non-alcoholic fatty liver diseases via in vivo and in vitro experiments

Article

Author: Zhang, Xin ; Zhou, Zhi-Jie ; Song, Guo-He ; Xiao, Chao ; Qiu, Chen ; Wang, Xiao-Liang ; Wang, Rui-Tao ; Deng, Gui-Long ; Wang, Yu-Peng ; Li, Zu-Yin ; Wu, Gang ; Yang, Yu-Long

BACKGROUNDThe lack of effective pharmacotherapies for nonalcoholic fatty liver disease (NAFLD) is mainly attributed to insufficient research on its pathogenesis. The pathogenesis of TM6SF2-efficient NAFLD remains unclear, resulting in a lack of therapeutic strategies for TM6SF2-deficient patients.AIMTo investigate the role of TM6SF2 in fatty acid metabolism in the context of fatty liver and propose possible therapeutic strategies for NAFLD caused by TM6SF2 deficiency.METHODSLiver samples collected from both NAFLD mouse models and human participants (80 cases) were used to evaluate the expression of TM6SF2 by using western blotting, immunohistochemistry, and quantitative polymerase chain reaction. RNA-seq data retrieved from the Gene Expression Omnibus database were used to confirm the over-expression of TM6SF2. Knockdown and overexpression of TM6SF2 were performed to clarify the mechanistic basis of hepatic lipid accumulation in NAFLD. MK-4074 administration was used as a therapeutic intervention to evaluate its effect on NAFLD caused by TM6SF2 deficiency.RESULTSHepatic TM6SF2 levels were elevated in patients with NAFLD and NAFLD mouse models. TM6SF2 overexpression can reduce hepatic lipid accumulation, suggesting a protective role for TM6SF2 in a high-fat diet (HFD). Downregulation of TM6SF2, simulating the TM6SF2 E167K mutation condition, increases intracellular lipid deposition due to dysregulated fatty acid metabolism and is characterized by enhanced fatty acid uptake and synthesis, accompanied by impaired fatty acid oxidation. Owing to the potential effect of TM6SF2 deficiency on lipid metabolism, the application of an acetyl-CoA carboxylase inhibitor (MK-4074) could reverse the NAFLD phenotypes caused by TM6SF2 deficiency.CONCLUSIONTM6SF2 plays a protective role in the HFD condition; its deficiency enhanced hepatic lipid accumulation through dysregulated fatty acid metabolism, and MK-4074 treatment could alleviate the NAFLD phenotypes caused by TM6SF2 deficiency.

01 Jul 2020·Cell Reports Medicine

Molecular Profiling Reveals a Common Metabolic Signature of Tissue Fibrosis

Article

Author: Sebhat, Iyassu K ; Previs, Stephen F ; Talukdar, Saswata ; Kan, Yanqing ; Muise, Eric S ; Devito, Kristine ; Imbriglio, Jason ; Costet, Philippe ; Zycband, Emanuel ; McLaren, David G ; Zhu, Yonghua ; Carballo-Jane, Ester ; Conway, James ; Shen, Xiao-Lan ; Jensen, Kristian K ; Tian, Ye ; Yi, Lan ; Peier, Andrea M ; Kutchukian, Peter S ; Smith, Elizabeth ; Zhang, Ji ; Shah, Kashmira ; Zhou, Haihong ; Ma, Li-Jun ; Hoek, Maarten ; Cai, Tian-Quan ; Han, Seongah ; Shah, Vinit ; Pinto, Shirly ; Huang, Yongcheng ; Saigal, Ashmita ; Akiyama, Taro E ; Chen, Ying

Fibrosis, or the accumulation of extracellular matrix, is a common feature of many chronic diseases. To interrogate core molecular pathways underlying fibrosis, we cross-examine human primary cells from various tissues treated with TGF-β, as well as kidney and liver fibrosis models. Transcriptome analyses reveal that genes involved in fatty acid oxidation are significantly perturbed. Furthermore, mitochondrial dysfunction and acylcarnitine accumulation are found in fibrotic tissues. Substantial downregulation of the PGC1α gene is evident in both in vitro and in vivo fibrosis models, suggesting a common node of metabolic signature for tissue fibrosis. In order to identify suppressors of fibrosis, we carry out a compound library phenotypic screen and identify AMPK and PPAR as highly enriched targets. We further show that pharmacological treatment of MK-8722 (AMPK activator) and MK-4074 (ACC inhibitor) reduce fibrosis in vivo. Altogether, our work demonstrate that metabolic defect is integral to TGF-β signaling and fibrosis.

01 Aug 2017·Cell MetabolismQ1 · BIOLOGY

Acetyl CoA Carboxylase Inhibition Reduces Hepatic Steatosis but Elevates Plasma Triglycerides in Mice and Humans: A Bedside to Bench Investigation

Q1 · BIOLOGY

Article

Author: Chakravarthy, Manu ; Burgess, Shawn C ; Addy, Carol ; Milstein, Stuart ; Deja, Stanislaw ; Kim, Chai-Wan ; Kusunoki, Jun ; Fitzgerald, Kevin ; Fu, Xiaorong ; Anderson, Norma N ; Previs, Steve ; Horton, Jay D ; Kelley, David E ; Ruddy, Marcie ; Li, Cai

Inhibiting lipogenesis prevents hepatic steatosis in rodents with insulin resistance. To determine if reducing lipogenesis functions similarly in humans, we developed MK-4074, a liver-specific inhibitor of acetyl-CoA carboxylase (ACC1) and (ACC2), enzymes that produce malonyl-CoA for fatty acid synthesis. MK-4074 administered to subjects with hepatic steatosis for 1 month lowered lipogenesis, increased ketones, and reduced liver triglycerides by 36%. Unexpectedly, MK-4074 increased plasma triglycerides by 200%. To further investigate, mice that lack ACC1 and ACC2 in hepatocytes (ACC dLKO) were generated. Deletion of ACCs decreased polyunsaturated fatty acid (PUFA) concentrations in liver due to reduced malonyl-CoA, which is required for elongation of essential fatty acids. PUFA deficiency induced SREBP-1c, which increased GPAT1 expression and VLDL secretion. PUFA supplementation or siRNA-mediated knockdown of GPAT1 normalized plasma triglycerides. Thus, inhibiting lipogenesis in humans reduced hepatic steatosis, but inhibiting ACC resulted in hypertriglyceridemia due to activation of SREBP-1c and increased VLDL secretion.

100 Deals associated with MK-4074

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Indication	Highest Phase	Country/Location	Organization	Date
Nonalcoholic Steatohepatitis	Phase 1	-	Merck Sharp & Dohme Corp.	26 Oct 2011
Diabetes Mellitus	Phase 1	US	Merck GmbH	-
Fatty Liver	Phase 1	US	Merck GmbH	-

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01431521 (4074-008, CTgov)	Phase 1	Metabolic dysfunction-associated steatotic liver disease	31	MK-4074 200 mg (MK-4074)	tjymtdfmpb(tcewuelsoz) = aifiggfpuf mxhkpcmewv (pyurisuabm, kgfmyjnmrd - xihynakmdj) View more	-	25 Mar 2016
				Pioglitazone hydrochloride 30 mg (Pioglitazone)	tjymtdfmpb(tcewuelsoz) = yppcxxtjfz mxhkpcmewv (pyurisuabm, ojugbxplfl - jutpqiccos) View more

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