Inhibition of ATP-citrate lyase improves NASH, liver fibrosis, and dyslipidemia

Morrow, Marisa R.; Batchuluun, Battsetseg; Wu, Jianhan; Ahmadi, Elham; Leroux, Julie M.; Mohammadi-Shemirani, Pedrum; Desjardins, Eric M.; Wang, Zhichao; Tsakiridis, Evangelia E.; Lavoie, Declan C.T.; Reihani, Amir; Smith, Brennan K.; Kwiecień, Jacek M.; Lally, James; Nero, Tracy L.; Parker, Michael W.; Ask, Kjetil; Scott, John W.; Jiang, Lei; Paré, Guillaume; Pinkosky, Stephen L.; Steinberg, Gregory R.

doi:10.1016/j.cmet.2022.05.004

Cited by 99 publications

(77 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, when D2O was used for measurements of DNL, no effect of ACLY depletion was observed, in contrast with the marked increase we report here (34). Lastly, while our manuscript was being revised, a paper published by Marrow et al (76) showing increased DNL gene expression, similar to our findings but surprisingly decreased glucose driven DNL and contrary to our finding decreased liver TG content in ACLY LKO mice on western diet supplemented by fructose in drinking water. They also reported increased fatty acid oxidation which might be the reason for the lower liver TG rather than the glucose driven DNL contribution.…”

Section: Discussionsupporting

confidence: 62%

Paradoxical activation of transcription factor SREBP1c and de novo lipogenesis by hepatocyte-selective ATP-citrate lyase depletion in obese mice

Yenilmez¹,

Kelly²,

Zhang³

et al. 2022

Journal of Biological Chemistry

View full text Add to dashboard Cite

Section: Discussionsupporting

confidence: 62%

Paradoxical activation of transcription factor SREBP1c and de novo lipogenesis by hepatocyte-selective ATP-citrate lyase depletion in obese mice

Yenilmez¹,

Kelly²,

Zhang³

et al. 2022

Journal of Biological Chemistry

View full text Add to dashboard Cite

“…We next focused on the role of PTH in the liver. Non-alcoholic liver steatosis results from abnormal lipid metabolism in the liver and eventually leads to liver injury ( 1 , 4 , 7 ). The hepatic fat vacuoles and accumulated lipid droplets in DIO mice shown by H&E and Oil Red O staining were reversed by PTH treatment ( Figure 2A ).…”

Section: Resultsmentioning

confidence: 99%

“…Non-alcoholic fatty liver disease is becoming a global concern and lacks licensed therapeutics at present ( 2 , 4 – 7 ). As James Black famously stated, “the best way to discover a new drug is to start with an old one” ( 44 ).…”

Section: Discussionmentioning

confidence: 99%

“…In recent years, the prevalence of the non-alcoholic fatty liver disease is increasing globally, and it is set out to be the predominant cause of chronic liver disease worldwide ( 2 , 3 ). However, effective and safe drugs for NAFLD are lacking at present ( 4 – 7 ). Thus, searching for agents efficiently targeting NAFLD is highly desirable.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Parathyroid hormone alleviates non-alcoholic liver steatosis via activating the hepatic cAMP/PKA/CREB pathway

Xiao

Guo

et al. 2022

Front. Endocrinol.

View full text Add to dashboard Cite

Non-alcoholic fatty liver disease (NAFLD), hallmarked by liver steatosis, is becoming a global concern, but effective and safe drugs for NAFLD are still lacking at present. Parathyroid hormone (PTH), the only FDA-approved anabolic treatment for osteoporosis, is important in calcium-phosphate homeostasis. However, little is known about its potential therapeutic effects on other diseases. Here, we report that intermittent administration of PTH ameliorated non-alcoholic liver steatosis in diet-induced obese (DIO) mice and db/db mice, as well as fasting-induced hepatic steatosis. In vitro, PTH inhibits palmitic acid-induced intracellular lipid accumulation in a parathyroid hormone 1 receptor (PTH1R)-dependent manner. Mechanistically, PTH upregulates the expression of genes involved in lipid β-oxidation and suppresses the expression of genes related to lipid uptake and de novo lipogenesis by activating the cAMP/PKA/CREB pathway. Taken together, our current finding proposes a new therapeutic role of PTH on NAFLD.

show abstract

“…On this matter, both the genetic inhibition of ACLY in hepatocytes and the pharmacological inhibition of ACLY by using bempedoic acid suppress fatty acid and cholesterol synthesis and increase fatty acid oxidation, while reducing glucose intolerance, liver steatosis and ballooning, without increasing circulating triglycerides. Moreover, studies in primary mouse and human stellate cells demonstrated that bempedoic acid also lowered liver fibrosis by downregulating pathways involved in collagen deposition [ 21 ••].…”

Section: Why a New Oral Non-statin Cholesterol-lowering Drug?mentioning

confidence: 99%

Bempedoic Acid: for Whom and When

Ruscica

Sirtori

Carugo

et al. 2022

Curr Atheroscler Rep

View full text Add to dashboard Cite

Purpose of Review The aim of creating an orally active non-statin cholesterol-lowering drug was achieved with bempedoic acid, a small linear molecule providing both a significant low-density lipoprotein cholesterol (LDL-C) reduction and an anti-inflammatory effect by decreasing high-sensitivity C-reactive protein. Bempedoic acid antagonizes ATP citrate-lyase, a cytosolic enzyme upstream of HMGCoA reductase which is the rate-limiting step of cholesterol biosynthesis. Bempedoic acid is a pro-drug converted to its active metabolite by very-long-chain acyl-CoA synthetase 1 which is present mostly in the liver and absent in skeletal muscles. This limits the risk of myalgia and myopathy. The remit of this review is to give clinical insights on the safety and efficacy of bempedoic acid and to understand for whom it should be prescribed. Recent Findings Bempedoic acid with a single daily dose (180 mg) reduces LDL-C by a mean 24.5% when given alone, by 18% when given on top of a major statin and by 38–40% when given in a fixed-dose combination with ezetimibe. Bempedoic acid does not lead to the risk of new-onset diabetes, and moderately improves the glycaemic profile. Summary The extensive knowledge on bempedoic acid mechanism, metabolism and side effects has led to an improved understanding of the potential benefits of this agent and offers a possible alternative to cardiologists and clinical practitioners somewhat worn out today by the occurrence of the muscular side effects of statins.

show abstract

Inhibition of ATP-citrate lyase improves NASH, liver fibrosis, and dyslipidemia

Cited by 99 publications

References 67 publications

Paradoxical activation of transcription factor SREBP1c and de novo lipogenesis by hepatocyte-selective ATP-citrate lyase depletion in obese mice

Paradoxical activation of transcription factor SREBP1c and de novo lipogenesis by hepatocyte-selective ATP-citrate lyase depletion in obese mice

Parathyroid hormone alleviates non-alcoholic liver steatosis via activating the hepatic cAMP/PKA/CREB pathway

Bempedoic Acid: for Whom and When

Contact Info

Product

Resources

About