Deregulation of Lipid Homeostasis: A Fa(c)t in the Development of Metabolic Diseases

Abstract

Lipids are important molecules for human health. The quantity and quality of fats consumed in the diet have important effects on the modulation of both the natural biosynthesis and degradation of lipids. There is an important number of lipid-failed associated metabolic diseases and an increasing number of studies suggesting that certain types of lipids might be beneficial to the treatment of many metabolic diseases. The aim of the present work is to expose an overview of de novo biosynthesis, storage, and degradation of lipids in mammalian cells, as well as, to review the published data describing the beneficial effects of these processes and the potential of some dietary lipids to improve metabolic diseases.

Keywords: dietary lipids; metabolism; mitofusin-2; phospholipids synthesis.

Figure 1

(A) Triglycerides (TAG) are synthetized by lipogenesis in the endoplasmic reticulum (ER) by esterification of three fatty acids with one molecule of glycerol. Lipids and enzymes (ER panel from left to right): FAs, fatty acids; FA-CoA, fatty-acyl-CoA; GPAT, glycerol-3-phosphate acyltransferase; LPA, lysophosphatidic acid; AGPAT, 1-acylglycerol-3-phosphate acyltransferase; PA, phosphatidate; PAP-1, phosphatidic acid phosphate; DAG, diacylglycerol; DGAT diacylglycerol acyltransferase. (B) Phospholipid synthesis de novo in mammalian cells takes place between the endoplasmic reticulum by the cytidine diphosphate (CDP)–Kennedy pathway and in mitochondria-associated membranes (MAMs), as discussed in the text. Phospholipids and enzymes from upper to bottom panel: P-C, phosphocholine; P-E, phosphoethanolamine; Pcyt1, choline-phosphate cytidylyltransferase; PCyt2, ethanolamine-phosphate cytidylyltransferase; PS, phosphatidylserine; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PSS1, PS synthase-1; PSS2, PS synthase-2; PEMT1, phosphatidylethanolamine N(PEN)-methyl transferase; Psid, mitochondrial phosphatidylserine decarboxylase.

Figure 2

Phosphatidylserine synthetized into the endoplasmic reticulum can be transferred into mitochondria through MAMs (mitochondria-associated membranes). PC, phosphatidylcholine; PE, phosphatidylethanolamine; PS, phosphatidylserine; MFN2, mitofusin 2; ORP5/8, oxysterol-binding protein-related protein 5/8.

Figure 3

(A) Lipid droplet synthesis. Neutral lipids are synthesized into the endoplasmic reticulum (ER) and accumulate between leaflets to form lipid lenses. Lipid accumulation deforms the ER until the lipid droplet (LD) buds from the ER to cytosol. LDs can increase its size by fusion with other LDs or TAG local accumulation. (B) Relevant metabolic diseases associated with increased lipid metabolism and lipids with a beneficial effect on metabolic diseases.