Lipogenesis inhibitors: therapeutic opportunities and challenges

Batchuluun, Battsetseg; Pinkosky, Stephen L.; Steinberg, Gregory R.

doi:10.1038/s41573-021-00367-2

Cited by 178 publications

(159 citation statements)

References 303 publications

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“…Thus, these are important contributors to the development of fatty liver [ 68 ]. An elevated insulin level is also a major cause of increased FAS and ACC levels in liver tissues [ 9 ]. Moreover, the CON ob / ob group showed increased expression of FAS and ACC without promotion of phosphorylation in the liver.…”

Section: Discussionmentioning

confidence: 99%

“…Due to a point mutation of the leptin gene, ob / ob mice are known to develop obesity, glucose intolerance, insulin resistance, and fatty liver [ 8 ]. Fatty livers of ob / ob mice show accumulation of triglycerides due to increased lipogenesis in parallel with elevated gene expression of lipogenic enzymes such as FAS and ACC by regulating SREBP transcription [ 9 ]. The adenosine monophosphate-activated protein kinase (AMPK) enzyme can act as an energy homeostasis sensor.…”

Section: Introductionmentioning

confidence: 99%

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Anti-Obesity and Anti-Hyperglycemic Effects of Meretrix lusoria Protamex Hydrolysate in ob/ob Mice

Kim

Chilakala

et al. 2022

IJMS

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Meretrix lusoria (M. lusoria) is an economically important shellfish which is widely distributed in South Eastern Asia that contains bioactive peptides, proteins, and enzymes. In the present study, the extracted meat content of M. lusoria was enzymatic hydrolyzed using four different commercial proteases (neutrase, protamex, alcalase, and flavourzyme). Among the enzymatic hydrolysates, M. lusoria protamex hydrolysate (MLPH) fraction with MW ≤ 1 kDa exhibited the highest free radical scavenging ability. The MLPH fraction was further purified and an amino acid sequence (KDLEL, 617.35 Da) was identified by LC-MS/MS analysis. The purpose of this study was to investigate the anti-obesity and anti-hyperglycemic effects of MLPH containing antioxidant peptides using ob/ob mice. Treatment with MLPH for 6 weeks reduced body and organ weight and ameliorated the effects of hepatic steatosis and epididymal fat, including a constructive effect on hepatic and serum marker parameters. Moreover, hepatic antioxidant enzyme activities were upregulated and impaired glucose tolerance was improved in obese control mice. In addition, MLPH treatment markedly suppressed mRNA expression related to lipogenesis and hyperglycemia through activation of AMPK phosphorylation. These findings suggest that MLPH has anti-obesity and anti-hyperglycemic potential and could be effectively applied as a functional food ingredient or pharmaceutical.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Anti-Obesity and Anti-Hyperglycemic Effects of Meretrix lusoria Protamex Hydrolysate in ob/ob Mice

Kim

Chilakala

et al. 2022

IJMS

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“…The main product of the DNS of FA is FA(16:0) 1 . So the main DNS route, plus elongation, starts at 16 carbons and then adds blocks of two carbons.…”

Section: Methodsmentioning

confidence: 99%

“…This represents the number of acetyl-CoA molecules used for the synthesis of an FA of length M. m is the number of 13 Elongation. The main product of the DNS of FA is FA(16:0) 1 . So the main DNS route, plus elongation, starts at 16 carbons and then adds blocks of two carbons.…”

Section: Estimation Of the Dnl Parametersmentioning

confidence: 99%

“…Fatty acids (FAs) are key metabolites that play a central role in cellular biology. FAs act as building blocks for the synthesis of complex lipids or as a source of energy, but also as signalling molecules 1 . Dysregulated FA metabolism has been associated with many of the most prevalent diseases, including obesity 2 , type 2 diabetes 3 , non-alcoholic fatty liver disease 4 or cancer 5 .…”

Section: Introductionmentioning

confidence: 99%

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FAMetA: a mass isotopologue-based tool for the comprehensive analysis of fatty acid metabolism

Alcoriza-Balaguer

García-Cañaveras

Benet

et al. 2022

Preprint

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The use of stable isotope tracers and mass spectrometry (MS) is the gold standard method for the analysis of fatty acids (FAs) metabolism. Yet current state-of-the-art tools provide limited information about FA biosynthetic routes. Here we present FAMetA, an R-package and a web-based application (www.fameta.es) that use 13C mass-isotopologue profiles to estimate not only FA import, synthesis and elongation, but also desaturation. The FAMetA workflow covers all the functionalities needed for MS data analyses. To illustrate its utility, different in vitro and in vivo experimental settings are used in which FA metabolism is modified. Thanks to the comprehensive characterisation of FA biosynthesis and the easy-to-interpret graphical representations compared to previous tools, FAMetA discloses unnoticed insights into how cells reprogramme their FA metabolism and, when combined with FASN, SCD1 and FADS2 inhibitors, it enables the straightforward identification of new FAs by the metabolic reconstruction of their synthesis route.

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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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Lipogenesis inhibitors: therapeutic opportunities and challenges

Abstract: Nonalcoholic fattly liver disease (NAFLD) includes a spectrum of metabolic diseases ranging from simple steatosis to cirrhosis in the liver.

Cited by 178 publications

References 303 publications

Anti-Obesity and Anti-Hyperglycemic Effects of Meretrix lusoria Protamex Hydrolysate in ob/ob Mice

Anti-Obesity and Anti-Hyperglycemic Effects of Meretrix lusoria Protamex Hydrolysate in ob/ob Mice

FAMetA: a mass isotopologue-based tool for the comprehensive analysis of fatty acid metabolism

Adenosine Triphosphate Citrate Lyase and Fatty Acid Synthesis Inhibition

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