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

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

doi:10.1016/j.cmet.2017.07.009

Cited by 315 publications

(312 citation statements)

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“…Although our data are consistent with studies documenting increased plasma triglycerides following ACC inhibition in humans and rodents, (15,41) there are several differences that warrant discussion. Studies generated from the Wakil laboratory were the first to report increased plasma triglycerides due to decreases in ACC activity.…”

Section: Discussionsupporting

confidence: 89%

“…To this end, hepatic DNL was assessed using deuterated water in highfructose-fed rats treated with ACCi or vehicle control ([10 mg/kg/day] × 6 days). Consistent with other reports, (15,23) ACCi treatment markedly reduced hepatic DNL and triglyceride content in a timedependent manner by 23% to 36% and 43% to 61%,…”

Section: Liver-directed Inhibition Of Acc Enhances Hepatic Ketogenesisupporting

confidence: 93%

“…Moreover, liver-directed inhibition of ACC has been associated with elevated plasma triglycerides in some patients. (15) To understand the mechanism for these observations, we examined the impact of Compound 1 on lipid and glucose metabolism in chow-fed rats and rodent models of DIO. Specifically, we demonstrate that acute treatment with Compound 1 significantly reduces hepatic ACC activity and malonyl-CoA levels in chow-fed rats.…”

Section: Discussionmentioning

confidence: 99%

“…The data presented demonstrate that liver-directed inhibition of ACC significantly reduces hepatic steatosis and hepatic insulin resistance; however, long-term treatment was paradoxically associated with increased plasma triglycerides, consistent with a recent report on a prior clinical candidate. (15) As such, we also evaluated the effect of ACC inhibition on triglyceride metabolism and the effect of coadministration of a fibrate to understand the mechanism for this observation.…”

Section: See Editorial On Page 2062mentioning

confidence: 99%

“…(32) Collectively, this gene signature is consistent with other reports documenting a derepression of LXR/SREBP1 target genes caused by reduced levels of polyunsaturated fatty acids (PUFAs). (15,33) Given that ACCi markedly reduces hepatic malonyl-CoA levels (Fig. 3C), it is possible that this leads to a decrease in PUFAs and subsequent up-regulation of nuclear hormone signaling that ultimately drives increased VLDL-triglyceride secretion and reduced lipid clearance.…”

Section: Disequilibrium Of Nuclear Hormone Receptor Regulation In Accmentioning

confidence: 99%

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Acetyl‐CoA Carboxylase Inhibition Reverses NAFLD and Hepatic Insulin Resistance but Promotes Hypertriglyceridemia in Rodents

et al. 2018

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Pharmacologic inhibition of acetyl-CoA carboxylase (ACC) enzymes, ACC1 and ACC2, offers an attractive therapeutic strategy for nonalcoholic fatty liver disease (NAFLD) through simultaneous inhibition of fatty acid synthesis and stimulation of fatty acid oxidation. However, the effects of ACC inhibition on hepatic mitochondrial oxidation, anaplerosis, and ketogenesis in vivo are unknown. Here, we evaluated the effect of a liver-directed allosteric inhibitor of ACC1 and ACC2 (Compound 1) on these parameters, as well as glucose and lipid metabolism, in control and diet-induced rodent models of NAFLD. Oral administration of Compound 1 preferentially inhibited ACC enzymatic activity in the liver, reduced hepatic malonyl-CoA levels, and enhanced hepatic ketogenesis by 50%. Furthermore, administration for 6 days to high-fructose-fed rats resulted in a 20% reduction in hepatic de novo lipogenesis. Importantly, long-term treatment (21 days) significantly reduced high-fat sucrose diet-induced hepatic steatosis, protein kinase C epsilon activation, and hepatic insulin resistance. ACCi treatment was associated with a significant increase in plasma triglycerides (approximately 30% to 130%, depending on the length of fasting). ACCi-mediated hypertriglyceridemia could be attributed to approximately a 15% increase in hepatic very low-density lipoprotein production and approximately a 20% reduction in triglyceride clearance by lipoprotein lipase (P ≤ 0.05). At the molecular level, these changes were associated with increases in liver X receptor/sterol response element-binding protein-1 and decreases in peroxisome proliferator-activated receptor-α target activation and could be reversed with fenofibrate co-treatment in a high-fat diet mouse model. Conclusion: Collectively, these studies warrant further investigation into the therapeutic utility of liver-directed ACC inhibition for the treatment of NAFLD and hepatic insulin resistance.

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Section: Discussionsupporting

confidence: 89%

Section: Liver-directed Inhibition Of Acc Enhances Hepatic Ketogenesisupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: See Editorial On Page 2062mentioning

confidence: 99%

Section: Disequilibrium Of Nuclear Hormone Receptor Regulation In Accmentioning

confidence: 99%

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Acetyl‐CoA Carboxylase Inhibition Reverses NAFLD and Hepatic Insulin Resistance but Promotes Hypertriglyceridemia in Rodents

et al. 2018

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Adenosine Triphosphate Citrate Lyase and Fatty Acid Synthesis Inhibition

Lau

Giugliano

2023

JAMA Cardiol

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ImportanceAdenosine triphosphate citrate lyase (ACLY) is a key regulatory enzyme of glucose metabolism, cholesterol and fatty acid synthesis, and the inflammatory cascade. Bempedoic acid, an ACLY inhibitor, significantly reduces atherogenic lipid markers, including low-density lipoprotein cholesterol (LDL-C), non–high-density lipoprotein cholesterol, and apolipoprotein B. Additional effects of ACLY inhibition include antitumor growth; reduction of triglycerides and proinflammatory molecules such as high-sensitivity C-reactive protein; less insulin resistance; reduction of hepatic lipogenesis; and weight loss.ObservationsWhile numerous ACLY inhibitors have been identified, most of the clinical data have focused on bempedoic acid. The Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen (CLEAR) program was a series of phase 3 clinical trials that evaluated its effects on lipid parameters and safety, leading to US Food and Drug Administration approval in 2020. CLEAR Outcomes was a phase 3, double-blind, randomized, placebo-controlled trial in individuals with a history of statin intolerance, serum LDL-C level of 100 mg/dL or higher, and a history of, or at high risk for, cardiovascular disease. Bempedoic acid modestly reduced the primary 4-way cardiovascular composite end point as well as the individual components of myocardial infarction and coronary revascularization but did not reduce stroke, cardiovascular death, or all-cause mortality. Rates of gout and cholelithiasis were higher with bempedoic acid, and small increases in serum creatinine, uric acid, and hepatic-enzyme levels were also observed.Conclusions and relevanceACLY inhibition with bempedoic acid has been established as a safe and effective therapy in high-risk patients who require further LDL-C lowering, particularly for those with a history of statin intolerance. The recently published CLEAR Outcomes trial revealed modest reductions in cardiovascular events with bempedoic acid, proportional to its LDL-C lowering, in high-risk individuals with statin intolerance and LDL-C levels of 100 mg/dL or higher. The additional effects of ACLY inhibition have prompted a more thorough search for novel ACLY inhibitors for conditions such as cancer, hypertriglyceridemia, chronic inflammation, type 2 diabetes, fatty liver disease, obesity, and metabolic syndrome. Similarly, therapies that reduce fatty acid synthesis are being explored for their use in cardiometabolic conditions.

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Therapeutic Approaches for Nonalcoholic Steatohepatitis (NASH)

Glatthar

Arch

2021

Burger's Medicinal Chemistry and Drug Discovery

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Nonalcoholic fatty liver disease (NAFLD), the most prevalent liver disease worldwide, is the hepatic manifestation of metabolic syndrome, which often also includes obesity, type 2 diabetes, and dyslipidemia. While NAFLD was thought to be nonprogressive, it has been shown in several studies that 12–40% of NAFLD patients develop its progressive form nonalcoholic steatohepatitis (NASH), which is characterized by inflammatory changes that can lead to progressive liver damage, fibrosis, cirrhosis, and hepatocellular carcinoma. There are presently no approved pharmacological agents for the treatment of NAFLD and NASH, but numerous agents are currently being investigated in clinical trials. These innovative therapies include three main approaches: inhibiting or reducing hepatic fat accumulation; ameliorating oxidative stress, inflammation, and apoptosis; and improving hepatic fibrosis by inhibition of fibrogenesis or promoting fibrolysis. This article provides a brief introduction to the underlying disease features and describes the medicinal chemistry and current status of the main low‐molecular‐weight pharmacological agents currently in development for NASH.

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

Cited by 315 publications

References 62 publications

Acetyl‐CoA Carboxylase Inhibition Reverses NAFLD and Hepatic Insulin Resistance but Promotes Hypertriglyceridemia in Rodents

Acetyl‐CoA Carboxylase Inhibition Reverses NAFLD and Hepatic Insulin Resistance but Promotes Hypertriglyceridemia in Rodents

Adenosine Triphosphate Citrate Lyase and Fatty Acid Synthesis Inhibition

Therapeutic Approaches for Nonalcoholic Steatohepatitis (NASH)

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