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The Stimulation of Steroid Biosynthesis by Luteinizing Hormone
Published in Mario Ascoli, Luteinizing Hormone Action and Receptors, 2019
Anita H. Payne, Patrick G. Quinn, John R. D. Stalvey
Intracellular cholesterol can be stored as cholesteryl esters in lipid droplets. The extent of cholesterol storage in gonads varies among different cell types in the same species. In a steroid hormone-producing cell, the amount of cholesterol stored as cholesteryl esters is dependent on the intracellular concentration of free cholesterol, which in turn is determined by the availability of exogenous cholesterol, by the endogenous synthesis of cholesterol, and by the rate of steroid hormone producton. There are two enzymes that are directly related to the amount of cholesterol stored as cholesteryl esters: acyl-coenzyme A:cholesterol acyltransferase (ACAT) and cholesteryl esterase (cholesteryl ester hydrolase). ACAT is associated with the smooth endoplasmic reticulum and catalyzes the esterification of free cholesterol; cholesteryl esterase catalyzes the hydrolysis of cholesteryl esters and is found predominantly in the cytosol.
Primary Prevention of Type 2 Diabetes
Published in Emmanuel C. Opara, Sam Dagogo-Jack, Nutrition and Diabetes, 2019
Natascha Thompson, Sam Dagogo-Jack
Current understanding indicates that multiple pathophysiological defects underlie T2DM (Figure 18.1). Generally, at least eight unique pathophysiological defects are currently recognized in T2DM: insulin resistance, impaired insulin secretion, impaired glucagon suppression, increased lipolysis, exaggerated hepatic glucose production, incretin deficiency/resistance, maladaptive renal glucose reabsorption, and central nervous system defects (including impaired dopaminergic tone and dysregulation of satiety) [12–14]. Insulin resistance can be inherited or acquired. Obesity, aging, physical inactivity, overeating, increased lipolysis, and accumulation of excessive amounts of nonesterified (free) fatty acids are known causes of insulin resistance. Normally, cytoplasmic long-chain fatty acids are transported into mitochondria as long-chain fatty acyl coenzyme A (LCFA-CoA) for beta-oxidation, a process that is gated by carnitine palmitoyl transferase (CPT)-1 and 2 (the shuttle enzymes located in the outer and inner mitochondrial membrane). This shuttle process ensures that fatty acids do not accumulate excessively in the cytoplasm. Inhibition of that process leads to intracellular accumulation of long-chain fatty acids, which can induce lipotoxicity, cellular dysfunction, and cell death [13,14]. Further, intracellular accumulation of long-chain fatty acids along with diacylglycerol (DAG) can activate certain isoforms of protein kinase C (PKC), leading to aberrant phosphorylation of the insulin receptor and consequent insulin resistance.
Substrates of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Pactimibe, a novel acyl coenzyme A:cholesterol acyltrans-ferase (ACAT) inhibitor developed for the treatment of hypercholesterolemia and atherosclerotic diseases, and its metabolite R-125528 are metabolized by CYP2D6 via ω-1 oxidation (Figure 3.91) (Kotsuma et al. 2008c). The Km value of R-125528 in CYP2D6-expressing microsomes is 1.74 μM, which is comparable to those of typical basic CYP2D6 substrates (1–10 μM). Pactimibe has a lower affinity than R-125528 to CYP2D6; however, the Km value is comparable to that of metoprolol.
The double-edged sword of probiotic supplementation on gut microbiota structure in Helicobacter pylori management
Published in Gut Microbes, 2022
Ali Nabavi-Rad, Amir Sadeghi, Hamid Asadzadeh Aghdaei, Abbas Yadegar, Sinéad Marian Smith, Mohammad Reza Zali
The gut microbiota plays a critical role in preserving the normal bioactivity of the host through gut microbiota-derived metabolites, especially bile acids (BAs), short-chain fatty acids (SCFAs), branched-chain amino acids (BCAAs), trimethylamine N-oxide (TMAO), tryptophan, and indole derivatives.35 Nevertheless, the knowledge concerning the direct effect of the gut microbiota on the host metabolism remains scarce; however, the gastrointestinal microbiota has a particular interaction with mitochondria owing to their common origin.36 It has been recently indicated that delta-valerobetaine production by the gut microbiome reduces cellular carnitine and mitochondrial long-chain acyl-coenzyme A (acyl-CoA); consequently, this obesogenic metabolite prevents mitochondrial fatty acid oxidation and leads to diet-dependent obesity.37
An evidence-based review of neuronal cholesterol role in dementia and statins as a pharmacotherapy in reducing risk of dementia
Published in Expert Review of Neurotherapeutics, 2021
Siddhartha Dutta, Sayeeda Rahman, Rahnuma Ahmad, Tarun Kumar, Gitashree Dutta, Sudeshna Banerjee, Abdullahi Rabiu Abubakar, Adekunle Babajide Rowaiye, Sameer Dhingra, Velayutham Ravichandiran, Santosh Kumar, Paras Sharma, Mainul Haque, Jaykaran Charan
Astrocytes recycle the cholesterol released from the brain’s degenerated nerve terminals [53]. In the adult brain, cholesterol synthesis and clearance are very sluggish. Apo E is synthesized by the astrocyte, which combines with the cholesterol and transports it out of the cell. The APOE–cholesterol (ApoE-Chol) complex is released from the astrocyte with ATP binding cassette transporters, ABCA1, and ABCG1 [54]. APOE behaves like a ligand for the LDL-receptor-related protein (LDLRP), a type of cell-surface-lipoprotein receptor expressed on the neuron [55,56]. The ApoE-Chol complex enters the neuron via the LDL receptors present on the neuron, and subsequently, internalization forms part of the endosomes, which ultimately fuse with lysosomes [57]. The lysosomes consist of acid lipase, which is involved in the hydrolysis of the ApoE-Chol complexes to release free cholesterol. The released cholesterol inside the cells is essential in synaptic and dendritic formation and remodeling [58]. The released cholesterol inside the cells offers negative feedback to the rate-limiting enzyme, HMG-CoA reductase, thus reducing the endogenous synthesis of cholesterol [40,51,55]. Acyl-coenzyme-A cholesterol acyltransferase (ACAT) is present in the endoplasmic reticulum. It esterifies the free cholesterol at the three positions to produce cholesterol esters that can help in more efficient storage of the cholesterol intracellularly (Figure 2) [55,57].
The mechanisms and therapeutic targets of ferroptosis in cancer
Published in Expert Opinion on Therapeutic Targets, 2021
Long Ye, Fengyan Jin, Shaji K. Kumar, Yun Dai
LPO is a well-defined driver of ferroptosis (Figure 1C). Peroxidized PUFAs can be catabolized into toxic aldol compounds containing epoxy-, oxy-, or aldehyde radicals. These radicals disrupt membrane integrity, thereby inducing mitochondrial contraction and cell membrane rupture[1]. The main PUFAs subjected to LPO include arachidonic acid (AA) and adrenaline (AdA). Acyl coenzyme A synthase long chain family member 4 (ACSL4) catalyzes the linkage of CoA to AA or AdA to form CoA-AA or CoA-AdA intermediates, which in turn form phosphatidylethanolamine(PE)-AA or PE-AdA by lysophosphatidylcholine acyltransferase 3 (LPCAT3). In the presence of lipoxygenases (LOXs), PE-AA or PE-AdA undergoes peroxidation, thus leading to ferroptosis[15]. Moreover, PUFAs also participate in ferroptosis through non-enzymatic autoxidation[4]. In this context, both decreased biosynthesis and increased degradation of PUFAs can inhibit ferroptosis. For example, monounsaturated FAs (MUFAs) antagonize ferroptosis by competing with PUFAs. In contrast, β-oxidation mediates the degradation of PUFAs, while its disruption leads to lipid accumulation[16].