Selective Acetyl-CoA Carboxylase 1 Inhibitor Improves Hepatic Steatosis and Hepatic Fibrosis in a Preclinical Nonalcoholic Steatohepatitis Model

Tamura, Yumiko Okano; Sugama, Jun; Iwasaki, Shinji; Sasaki, Masako; Yasuno, Hironobu; Aoyama, Kazunobu; Watanabe, Masanori; Erion, Derek M.; Yashiro, Hiroaki

doi:10.1124/jpet.121.000786

Cited by 15 publications

(7 citation statements)

References 40 publications

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“…However, Goedeke et al reported that dual inhibition of ACC1 and ACC2 also resulted in plasma hypertriglyceridemia from a combination of increased hepatic very-low-density lipoprotein production and a decrease in triglyceride clearance by lipoprotein lipase (LPL) [ 119 ]. Selective ACC1 inhibitors have also been utilized to treat MAFLD in a mouse model of genetic fatty liver [ 120 ]. Clinical trials utilizing dual ACC inhibitors alone or in combination with diacylglycerol O-acetyltransferase 2 (DGAT2) are currently underway in adults with MAFLD [ 121 ].…”

Section: A Mechanistic View Of Therapies For Mafldmentioning

confidence: 99%

Molecular mechanisms of metabolic associated fatty liver disease (MAFLD): functional analysis of lipid metabolism pathways

et al. 2022

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The metabolic-associated fatty liver disease (MAFLD) is a condition of fat accumulation in the liver in combination with metabolic dysfunction in the form of overweight or obesity and insulin resistance. It is also associated with an increased cardiovascular disease risk, including hypertension and atherosclerosis. Hepatic lipid metabolism is regulated by a combination of the uptake and export of fatty acids, de novo lipogenesis, and fat utilization by β-oxidation. When the balance between these pathways is altered, hepatic lipid accumulation commences, and long-term activation of inflammatory and fibrotic pathways can progress to worsen the liver disease. This review discusses the details of the molecular mechanisms regulating hepatic lipids and the emerging therapies targeting these pathways as potential future treatments for MAFLD.

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Section: A Mechanistic View Of Therapies For Mafldmentioning

confidence: 99%

Molecular mechanisms of metabolic associated fatty liver disease (MAFLD): functional analysis of lipid metabolism pathways

et al. 2022

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“…We believe this beneficial effect is primarily due to inhibition of de novo lipogenesis; however, reduced production of malonyl-CoA would also increase the mitochondrial import and oxidation of fatty acids. Although extrapolating these findings to DM1-related NAFLD in humans is not straightforward, pharmacologic inhibition of ACC is currently viewed as one of the most promising therapeutic approaches for treating NAFLD/NASH [81][82][83][84][85] . It is important to note that a small proportion of NAFLD patients treated with ACC inhibitors may experience hypertriglyceridemia over time, which can increase their risk of developing cardiovascular disease [86][87][88] .…”

Section: Discussionmentioning

confidence: 99%

Altered drug metabolism and increased susceptibility to fatty liver disease in myotonic dystrophy

Dewald

Gupta

et al. 2021

Preprint

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Myotonic Dystrophy type 1 (DM1) is multi-systemic muscular dystrophy, affecting 1 in 3000 people, characterized by muscle wasting, myotonia, cardiac and gastrointestinal abnormalities and cognitive impairment, among other symptoms. DM1 is caused by a (CTG)n repeat expansion in the 3’ UTR of the ubiquitously expressed gene DMPK. The (CUG)n containing RNAs resulting from the transcription of this diseased DMPK gene aggregate in the nucleus, forming foci which sequester muscleblind-like (MBNL) family proteins, a group of splicing factors that play significant roles in the juvenile-to-adult development of many tissues. Recent studies show that DM1 patients have increased susceptibility toward glucose intolerance, non-alcoholic fatty liver disease (NAFLD), and metabolic syndrome. Furthermore, DM1 patients are abnormally sensitive to a wide range of analgesics and anesthetics, with complications ranging from prolonged anesthesia recovery to heightened pulmonary dysfunction. These findings suggest a predisposition for liver damage and dysfunction in DM1 patients; however, this possibility has gone uninvestigated. To understand the effects of DM1 in the liver, we generated a hepatocyte-specific DM1 mouse model in which we can induce the expression of CUG containing RNA, specifically in the liver. Through these mice, we demonstrate that the expression of the toxic RNA in hepatocytes sequesters MBNL proteins, causing a reduction in mature hepatocellular activity, however, we find that, in contrast to other tissues, loss of MBNL1 activity only reproduces a small portion of the transcriptome changes in DM1 afflicted hepatocytes. We characterized the transcriptomic changes driven by DM1 in the liver and show that these lead to changes in hepatocellular morphology, inflammation, and necrosis, as well as excessive lipid accumulation and fatty liver disease. We further demonstrate that DM1 mice livers are defective in drug metabolism and clearance, and when challenged, exhibit marked impairment against zoxazolamine-induced paralysis and acetaminophen-induced hepatotoxicity. Together, these results reveal that the expression of CUG repeat containing RNA disrupts the normal hepatic functions and predisposes the liver to injury, fatty liver disease, and drug clearance pathologies that may jeopardize the health of DM1 patients and complicate the treatment of DM1.

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“…Moreover, it is shown that the selectively inhibition of ACC2 may be ineffective in treating some metabolic diseases (114). A selective inhibitor targeting ACC1 that shows anti-NAFLD/ NASH effects in pre-clinical models is reported in a recent study (115), which is expected to strengthen the efficacy.…”

Section: Limitations and Prospectsmentioning

confidence: 96%

Acetyl-CoA Carboxylases and Diseases

Wang

et al. 2022

Front. Oncol.

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Acetyl-CoA carboxylases (ACCs) are enzymes that catalyze the carboxylation of acetyl-CoA to produce malonyl-CoA. In mammals, ACC1 and ACC2 are two members of ACCs. ACC1 localizes in the cytosol and acts as the first and rate-limiting enzyme in the de novo fatty acid synthesis pathway. ACC2 localizes on the outer membrane of mitochondria and produces malonyl-CoA to regulate the activity of carnitine palmitoyltransferase 1 (CPT1) that involves in the β-oxidation of fatty acid. Fatty acid synthesis is central in a myriad of physiological and pathological conditions. ACC1 is the major member of ACCs in mammalian, mountains of documents record the roles of ACC1 in various diseases, such as cancer, diabetes, obesity. Besides, acetyl-CoA and malonyl-CoA are cofactors in protein acetylation and malonylation, respectively, so that the manipulation of acetyl-CoA and malonyl-CoA by ACC1 can also markedly influence the profile of protein post-translational modifications, resulting in alternated biological processes in mammalian cells. In the review, we summarize our understandings of ACCs, including their structural features, regulatory mechanisms, and roles in diseases. ACC1 has emerged as a promising target for diseases treatment, so that the specific inhibitors of ACC1 for diseases treatment are also discussed.

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Selective Acetyl-CoA Carboxylase 1 Inhibitor Improves Hepatic Steatosis and Hepatic Fibrosis in a Preclinical Nonalcoholic Steatohepatitis Model

Cited by 15 publications

References 40 publications

Molecular mechanisms of metabolic associated fatty liver disease (MAFLD): functional analysis of lipid metabolism pathways

Molecular mechanisms of metabolic associated fatty liver disease (MAFLD): functional analysis of lipid metabolism pathways

Altered drug metabolism and increased susceptibility to fatty liver disease in myotonic dystrophy

Acetyl-CoA Carboxylases and Diseases

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