ReviewDe novo lipogenesis in health and disease
Introduction
De novo lipogenesis (DNL) or de novo fatty acid (FA) synthesis is the metabolic pathway that synthesizes fatty acids from excess carbohydrates. These fatty acids can then be incorporated into triglycerides (TGs) for energy storage. In normal conditions DNL mainly takes place in liver and adipose tissue and is considered to be a minor contributor in maintenance of serum TG homeostasis [1]. While most of the serum TG content is obtained from dietary sources [1]. However, some studies suggest that hepatic DNL could make significant contribution to serum lipid content in individuals on high carbohydrate diet [2]. The flow of carbons from glucose to fatty acids, which is modulated by the lipogenic pathway, includes a coordinated series of enzymatic reactions. The first step of this series of reactions is the conversion of citrate to acetyl-CoA by ATP-citrate lyase (ACLY). The resulting acetyl-CoA is carboxylated to malonyl-CoA by acetyl-CoA carboxylase (ACACA). Fatty acid synthase (FASN) is the key rate-limiting enzyme that brings about the conversion of malonyl-CoA into palmitate (Fig. 1). After a series of reactions palmitate is further converted into complicated fatty acids. The main product of DNL is palmitate but stearate and shorter fatty acids are also generated.
Deregulations in the lipogenic pathway are observed in certain pathological or physiological conditions. The irregularities of DNL in the key lipogenic tissues could disrupt the usual lipid homeostasis in the body. In addition to that the non-lipogenic tissues – where DNL is suppressed under normal conditions – could exhibit up-regulation of this pathway. This inapt activity of lipogenesis in ordinarily non-lipogenic tissues could be caused by viral infections or by malignant transformation of normal cells. The present review highlights different factors affecting the de novo lipogenesis with the special focus on deregulation of this pathway in various physiological conditions.
Section snippets
Regulation of de novo lipogenesis
In human body the lipogenic pathway is active at least in the major metabolic tissues — liver and adipose tissue. However, hepatic lipogenesis is shown to be quantitatively more efficient than lipogenesis in the adipose tissue [3]. In fact FASN – which is considered as a marker for lipogenesis – has been categorized as a housekeeping protein in the liver [4].
DNL has previously been shown to be highly responsive to changes in the dietary regimen. For instance high-carbohydrate diets are shown to
Aberration of de novo lipogenesis in major metabolic tissues: Causes and Consequences
The deregulation of DNL in the major lipogenic tissues of the human body is often observed in various metabolic anomalies (Table 1 [5], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34]). One of the most common conditions associated with deregulated DNL is insulin resistance — condition in which cells fail to respond to the normal actions of insulin and that precedes the development of type 2 diabetes [4]. The pathogenesis of insulin resistance is a complex process. It has been
Aberration of de novo lipogenesis in non-metabolic tissues: Cause and Consequences
As discussed above viral infections are shown to induce increase in hepatic DNL and consequent elevation in the serum lipid levels [30]. In addition to that infections by divergent viruses are reported to induce de novo lipogenesis in the infected cells. This observation is consistent with the fact that viruses rely on the metabolic network of their cellular hosts to provide energy and building blocks required for the viral replication. Previous works have reported that numerous different
Therapeutic targeting of DNL
As discussed above de novo lipogenesis is reported to be exacerbated in cancer tissues, certain virus infected cells etc. In addition to that deregulated DNL in the major lipogenic tissues is often associated with other metabolic anomalies — such as obesity, NAFLD and type 2 diabetes. These observations suggest that inhibitors of the DNL pathway may have substantial therapeutic significance.
Several research groups have shown that therapeutic targeting of various enzymes of this pathway such as
Conclusion
De novo lipogenesis is a complex and highly regulated pathway that can lead to adverse metabolic consequences when deregulated. The deregulation of DNL in the major lipogenic tissues of the human body is often observed in various metabolic anomalies — including obesity, non-alcoholic fatty liver disease and metabolic syndrome. In addition to that de novo lipogenesis is reported to be exacerbated in cancer tissues and virus infected cells. Previous reports have identified fatty acid synthesis as
Disclosure statement
The authors have nothing to disclose.
Acknowledgments
Work from author’s laboratory was supported by: Higher Education Commission, Pakistan (N.Zaidi).
Doctoral Program Co-ordination Committee, University of the Punjab, Lahore, Pakistan (F. Ameer).
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