Primary Prevention of Type 2 Diabetes
Emmanuel C. Opara, Sam Dagogo-Jack in Nutrition and Diabetes, 2019
Acetyl-CoA, a product of glycolysis for the Krebs cycle, can be converted to malonyl CoA by the enzyme acetyl-CoA carboxylase (ACC). Malonyl-CoA is the activated two-carbon donor required for fatty acid synthesis. Malonyl-CoA also is a potent inhibitor of CPT-1, thereby blocking the delivery and oxidation of fatty acids in mitochondria. The result is accumulation of long-chain fatty acids in the cytosol and eventual lipotoxicity [14,15]. Glucose abundance also increases the formation of intracellular DAG. Thus, multiple metabolic pathways link intracellular glucose abundance (usually derived from carbohydrate consumption) to impaired fat oxidation, fatty acid synthesis, accumulation of long-chain fatty acids, risk of lipotoxicity, and insulin resistance. Among the potent interventions that have been demonstrated to ameliorate the pathological cellular and molecular processes leading to insulin resistance are caloric restriction (reduction of carbohydrate and fat intake), physical activity, and weight loss [16–24].
Inhibiting Insulin Resistance and Accumulation of Triglycerides and Cholesterol in the Liver
Christophe Wiart in Medicinal Plants in Asia for Metabolic Syndrome, 2017
Rheum tanguticum Maxim. ex Balf. contains rhaponticin (Figure 3.5) that given orally to spontaneous type 2 diabetic obese KK-Ay diabetic mice at a dose of 125 mg/kg/day for 28 days lowered glycaemia and insulinaemia by more than 50%.111 This stilbene glucoside reduced serum cholesterol and triglycerides and lowered low-density lipoprotein by more than 60% and decreased plasma nonesterified free fatty acids by more than 50%.111 Furthermore, this treatment increased pancreatic and liver weight and reduced serum aspartate aminotransferase and alanine aminotransferase, whereby hepatic glycogen increased by more than 2 folds.111 In hepatocytes, glycolysis of glucose yields pyruvic acid which, in mitochondria, is converted into citric acid. In the cytosol, citric acid is converted to acetyl-CoA by ATP citrate lyase.112 Acetyl-CoA is serves as substrate for the synthesis of malonyl-CoA by acetyl-CoA carboxylase, and fatty acid synthetase use both acetyl-CoA and malonyl-CoA for the construction of fatty acids.112 Desoxyrhaponticin and rhaponticin from the rhizomes of Rheum tanguticum Maxim. ex Balf. contain inhibited fatty acid synthetase with IC50 values of 172.6 and 73.2 µM in vitro.113 In MCF-7 cells, these stilbenes decreased fatty acid synthetase expression and enzymatic activities were reduced to 13% and 51%, respectively, at the concentration of 400 µM.113
Carnitine palmitoyl transferase I deficiency
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop in Atlas of Inherited Metabolic Diseases, 2020
Three isoforms of CPT I have been identified [8]. Type IA or H-I, the hepatic isoform, the key regulator of fatty acid metabolism, is defective in CPT I deficiency. It transports long-chain fatty acyl CoAs across the outer mitochondrial membrane. Affected infants have hypoketotic hypoglycemia, but often remain otherwise well. Newborn screening tests reveal elevated free carnitine (elevated C0/C16 + C18). Confirmation of the leukocyte diagnosis is accomplished by assay of the enzyme in fibroblasts. The disorder is detected by newborn screening, with variable sensitivity [9]. Type IB (M-I) is expressed in skeletal muscle. Fatty acid synthesis in the central nervous system is implicated in the control of food intake and energy expenditure. Malonyl CoA is an intermediate in this pathway. Malonyl CoA is an inhibitor of CPT I. CPT Ic knock out (KO) mice have lower body weight and food intake, and this is consistent with the function of malonyl CoA as an energy sensor. Paradoxically, CPT Ic KO mice fed a high-fat diet become obese and have decreased rates of fatty acid oxidation [10]. CPT Ic is found in the brain. Following a high-fat intake, CPT Ic KO mice developed severe insulin resistance, which was considered a result of increased hepatic gluconeogenesis and decreased uptake of glucose by skeletal muscle. Elevated concentrations of nonesterified fatty acids in plasma are thought to be important mediators [11]. Overexpression of CPT Ic in hypothalamus after injection of a CPT Ic adenoviral vector protects mice from obesity [12], confirming a role for CPT Ic in energy homeostasis.
Acetyl-CoA carboxylase (ACC) as a therapeutic target for metabolic syndrome and recent developments in ACC1/2 inhibitors
Published in Expert Opinion on Investigational Drugs, 2019
Leyuan Chen, Yuqing Duan, Huiqiang Wei, Hongxin Ning, Changfen Bi, Ying Zhao, Yong Qin, Yiliang Li
Clinical research on ACC inhibitors in the field of cancer will face both opportunities and challenges. On the one hand, although the types and causes of cancer are ever-changing, the changes in metabolic pathways in cancer cells have certain similarities. Changes in fatty acid metabolism pathways not only provide energy for the development of cancer, but also play an important role in biofilm macromolecules and signaling molecules [98–100]. This provides new ideas for treating cancer by cutting off cancer cell energy pathways. On the other hand, the direct catalytic product of ACC, malonyl-CoA, is an important signaling molecule in normal cells, which plays an important role in stimulation of B cell insulin secretion by glucose and hypothalamic control of appetite [98]. In addition, a decrease in the level of malonyl-CoA inhibits the synthesis of polyunsaturated fatty acids. Therefore, like MK-4074, excessive inhibition of ACC may lead to obvious metabolic abnormalities and partial inhibition may be difficult to achieve the best anti-tumor effect. The balance between a certain degree of ACC inhibition and negative effects on metabolism is important.
Gene expression profiling of rat livers after continuous whole-body exposure to low-dose rate of gamma rays
Published in International Journal of Radiation Biology, 2018
Kim Ngan Tran, Jong-il Choi
The conversion of acetyl-CoA into malonyl-CoA is regulated by acetyl-CoA carboxylase 1 (ACC1) or ACC2. The latter is thought to control mitochondrial fatty acid oxidation by means of the ability of malonyl-CoA to inhibit carnitine palmitoyltransferase I (Cpt1), the rate-limiting step in fatty acid uptake and oxidation by mitochondria (He et al. 2013). Acacb which encoded for ACC2 was down-regulated while Cpt1 was up-regulated significantly. Pentose phosphate pathway is the major source of NADPH, which is required for anabolic reactions such as fatty acid synthesis and the reduction of glutathione (Klepper 2013). In this study, the only two NADPH-generating steps of the pathway, G6PD and PGD, were both transcriptionally down-regulated. Notably, G6PD is also the rate-limiting reaction in the pentose phosphate pathway under physiological conditions.
The effect of adenosine monophosphate-activated protein kinase on lipolysis in adipose tissue: an historical and comprehensive review
Published in Archives of Physiology and Biochemistry, 2022
Daniel Boone-Villa, Janeth Ventura-Sobrevilla, Asdrúbal Aguilera-Méndez, Joel Jiménez-Villarreal
AMPK can be activated in AT by exercise, fasting and cold exposure (Park et al.2002, Daval et al.2005, Sponarova et al.2005, Mulligan et al.2007), inducing a decrease in malonyl CoA concentrations by acetyl CoA carboxylase type 1 (ACC1) phosphorylation. AMPK stimulates internalisation of NEFA by translocation of vesicles that contain CD36 transporter to the cell membrane (Habets et al.2009). AMPK also promotes the internalisation of fatty acids into the mitochondrion to produce energy through the β-oxidation pathway. This process is initiated by the phosphorylation of ACC type 2 (ACC2). This phosphorylation reduces the activity of the enzyme and subsequently results in a decrease of malonyl CoA concentration. The decrease of malonyl CoA concentrations allows the entrance of fatty acids into the mitochondrial matrix by way of the carnitine palmitoyl transferase 1 and 2 (CPT1 and CPT2) (Merrill et al.1997).
Related Knowledge Centers
- Acyl Carrier Protein
- Bicarbonate
- Coenzyme A
- Fatty Acid Synthesis
- Polyketide
- Malonic Acid
- Acetyl-Coa
- Acetyl-Coa Carboxylase
- Adenosine Triphosphate
- Thiol