Entrance of Electrons to Acyl-CoA Desaturation

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Austin J Mol & Cell Biol. 2015; 2(1): 1005.

Entrance of Electrons to Acyl-CoA Desaturation

Csala M*

Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Hungary

*Corresponding author: Csala M, Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, H-1444 Budapest, POB 260, Hungary

Received: October 04, 2015; Accepted: October 26, 2015; Published: October 28, 2015


Deleterious effects of excessive Free Fatty Acid (FFA) supply have been widely studied and are referred to as lipotoxicity. FFA-induced signaling alterations and complex metabolic stress contribute to the increased incidence of various pathologies (e.g. diabetes, cardiovascular diseases and cancer) in obese people. Unsaturated fatty acids are less toxic, and they can reduce the damage caused by saturated ones, and this highlights acyl-CoA desaturation as a cellular defense mechanism. The rate limiting Stearoyl-CoA Desaturase 1 (SCD1) is embedded in the Endoplasmic Reticulum (ER) membrane, and it was known to receive electrons from cytosolic NADH and NADPH. The novel NADH Cytochrome b5 Oxidoreductase (Ncb5or) is assumed to serve as an alternative electron supplier of acyl-CoA desaturases in various tissues. The protein interactions and exact metabolic function of Ncb5or remain to be elucidated. Since the separate pyridine nucleotide pool of the ER lumen is a major determinant of pre-receptor glucocorticoid activation, it’s possible connection with acyl-CoA desaturation is of great importance.

Keywords: Saturated fatty acid; Endoplasmic reticulum; Diabetes; Stress; Insulin resistance; Beta cell dysfunction


ATF6: Activating Transcription Factor 6; b5: Cytochrome b5; b5R: Cytochrome b5 Reductase; FFA: Free Fatty Acid; H6PD: Hexose 6-Phosphate Dehydrogenase; 11βHSD1: Type 1 11β-Hydroxysteroid Dehydrogenase; IRE1: Inositol-Requiring Enzyme 1; JNK: c-Jun Amino-terminal Kinase; MAPK: Mitogen-Activated Protein Kinase; Ncb5or: NADH Cytochrome b5 Oxidoreductase; PERK RNADependent Protein Kinase-Like ER Kinase; PKC: Protein Kinase C; ROS: Reactive Oxygen Species; SCD1: Stearoyl-CoA Desaturase 1; SFA: Saturated Fatty Acid; UFA: Unsaturated fatty acid; UPR: Unfolded Protein Response


Fatty acids are superb sources of metabolic energy in most aerobic cells of the human body. Some tissues, such as the brain have restricted access to plasma lipids due to the presence of special barriers, but others can receive these nutrients either from plasma lipoproteins (i.e. VLDL and Chylomicron) or directly as non-esterified Free Fatty Acids (FFAs). FFAs are largely associated to serum albumin and they are normally available in prolonged starvation (or physical activity) when the fatty acid stores are mobilized and triglycerides are intensively hydrolyzed in the adipocytes [1]. Fat mobilization and FFA secretion are stimulated by low insulin/glucagon ratio and by certain stress hormones, e.g. glucocorticoids and catecholamines. Elevation of FFA levels, therefore, does not normally coincide with insulin action. Obesity and a consequent local inflammation in the adipose tissue can lead to a sustained plasma free fatty academia, which is implicated in the development of diabetes [2] as well as in the increased risk to certain types of cancer [3] observed in obese patients.


Excessive supply of FFA causes a stress of multiple components in the cells of most non-adipose tissues. The damage can result in cellular dysfunction or even in programmed cell death, i.e. lipotoxicity or lipoapoptosis [4]. Upon reaching the outer surface of the plasma membrane, fatty acid molecules can modulate inflammatory signaling through binding to Toll-like receptors [5]. Once taken up into the cytosol, fatty acids are activated to acyl-CoA, an intermediate readily available for synthetic or catabolic purposes. Intensified β-oxidation and coupled oxidative phosphorylation are accompanied by enhanced Reactive Oxygen Species (ROS) generation, which underlies the FFAinduced oxidative stress [6].

Lipotoxicity also involves derangements in the Endoplasmic Reticulum (ER). Permeability of the ER membrane is remarkably increased by long chain acyl-CoA-s at higher concentrations [7], and this causes a disturbance in the luminal milieu [8], primarily in the calcium homeostasis of the organelle. Ca2+ leak interferes with microsomal protein processing as many of the ER chaperones and foldases are calcium-dependent [9]. The consequent accumulation of immature polypeptides in the lumen is sensed by three transmembrane ER stress receptors: RNA-dependent Protein Kinase-like ER Kinase (PERK), Inositol-Requiring Enzyme 1 (IRE1) and Activating Transcription Factor 6 (ATF6). The three largely interacting signaling pathways triggered by these sensors govern major rearrangements in the cellular functions and they are collectively referred to as the Unfolded Protein Response (UPR). Although the primary aim of the UPR is to restore the balance of protein load and protein folding in the ER, it also contributes to insulin resistance and apoptosis [10]. The role of lipotoxicity-induced ER stress in β-cell dysfunction has also been revealed, and attenuation of the UPR has been implicated in the β-cell-protective effect of the antidiabetic drug metformin [11].

Oxidative and ER stress as well as pro-inflammatory stimuli synergistically activate certain members of the Mitogen Activated Protein Kinase (MAPK) family, particularly the c-Jun Amino- Terminal Kinase (JNK). Lipotoxic JNK activation is further supported by diglyceride and ceramide accumulation through atypical Protein Kinase C (PKC) isoforms [12]. The central role of JNK in obesityrelated insulin resistance and diabetes [13] as well as in tumor development and progression [14] has been widely investigated.

Protective role of Fatty Acid Desaturation

It has been demonstrated by several in vivo and in vitro studies that saturated fatty acids (SFAs, e.g., palmitate and stearate) are more toxic than the mono- or poly-unsaturated ones (UFAs, e.g. oleate or linoleate). Moreover, the simultaneously administered UFAs can reduce SFA-induced dysfunctions and injuries. This intriguing phenomenon is partly due to the dominant pro-inflammatory nature of SFAs and anti-inflammatory actions of UFAs, especially n-3 polyunsaturated ones [15]. It became also evident that UFAs are required for an efficient channeling of SFAs to triglyceride synthesis, which serves as a defense mechanism to prevent a deleterious accumulation of saturated acyl-CoA intermediates [4,16]. In addition, IRE1 and PERK can be activated by increased lipid saturation in the ER membrane. Therefore, the ratio of saturated and unsaturated fatty acids in the cell can modulate the UPR signaling through the lipid sensitivity of the transmembrane domains of these receptors [17].

In case of unbalanced supply of SFAs, the intrinsic ability of the cells to insert double bonds into the fatty acyl chains remains the only means to produce protective UFAs and maintain triglyceride synthesis. Human cells employ Stearoyl-CoA Desaturase 1 (SCD1) enzyme to convert stearoyl-CoA (18:0) or palmitoyl-CoA (16:0) to Δ9 mono-unsaturated derivatives, oleyl-CoA (18:1 n9) or palmioleyl- CoA (16:1 n9), respectively [18]. This enzyme is embedded in the ER membrane and receives electrons from NADH or NADPH through the concerted action of two associated membrane proteins, the flavoprotein cytochrome b5 Reductase (b5R) and the hemoprotein cytochrome b5 (b5) (Figure 1). The protective role of SCD1 has been demonstrated in different models of palmitate-induced lipotoxicity [19,20].

Citation: Csala M. Entrance of Electrons to Acyl-CoA Desaturation. Austin J Mol & Cell Biol. 2015; 2(1): 1005.