Involvement of a battery of investigated genes in lipid droplet pathophysiology and associated comorbidities

Abstract

Lipid droplets (LDs) are highly specialized energy storage organelles involved in the maintenance of lipid homoeostasis by regulating lipid flux within white adipose tissue (WAT). The physiological function of adipocytes and LDs can be compromised by mutations in several genes, leading to NEFA-induced lipotoxicity, which ultimately manifests as metabolic complications, predominantly in the form of dyslipidemia, ectopic fat accumulation, and insulin resistance. In this review, we delineate the effects of mutations and deficiencies in genes - CIDEC, PPARG, BSCL2, AGPAT2, PLIN1, LIPE, LMNA, CAV1, CEACAM1, and INSR - involved in lipid droplet metabolism and their associated pathophysiological impairments, highlighting their roles in the development of lipodystrophies and metabolic dysfunction.

Keywords: Lipid droplet formation; adipogenesis; insulin resistance; lipid droplet hydrolysis; lipodystrophy.

Figure 1.

Functional significance of LD-proteins in lipid metabolism and potential aberrations. NEFAs mediate insulin resistance by hindering insulin-induced glucose uptake and glycogen synthesis. Simultaneously, NEFAs drive glucose-stimulated insulin secretion. This nuance is crucial, as it implies that insulin resistance would not necessarily lead to diabetes as long as NEFA-mediated insulin secretion is able to compensate for NEFA-induced insulin resistance [5,6]. Abbreviations: I.R., insulin resistance; I.S., insulin secretion; LD, lipid droplet; LD-proteins, lipid droplet associated proteins; NEFA, non-esterified (free) fatty acids (plasma-circulating); T2DM, type 2 diabetes Mellitus; TAG, Triacylglycerol; WAT, white adipose tissue.

Figure 2.

Insulin signalling triggers lipid droplet fusion. Insulin-induced anti-apoptosis and lipid droplet formation by differential regulation of CIDEA and CIDEC via Akt1/2 and JNK2-dependent pathways, respectively, in human adipocytes. CIDEC mediates lipid droplet fusion via gel-like condensation on lipid droplet cell surface. Figure readapted from [24] and [26]. Abbreviations: AKT/PKB, protein kinase B; I.R., insulin receptor; I.R.S., insulin receptor substrate; JNK2, c-Jun N-terminal kinase 2; LD, lipid droplet; LDCS, lipid droplet contact site; PI3K, phosphatidylinositol 3-kinase; WAT, white adipose tissue.

Figure 3.

Mobilization of TAGs in lipid droplets of white adipose tissue. Abbreviations: ADP, Adenosine diphosphate; ATGL, adipose triglyceride lipase; ATP, Adenosine triphosphate; cAMP, cyclic Adenosine monophosphate; CGI-58, comparative gene identification-58 (co-activator of ATGL); DAG, Diacylglycerol; FFA, free fatty Acids; HSL, hormone sensitive lipase; MAG, Monoacylglycerol; MGL, monoglyceride lipase; NEFA, non-esterified fatty acids; PKA, protein kinase A; PLIN, perilipin-1; TAG, Triacylglycerol.

Figure 4.

The journey of insulin. Insulin is discharged from the pancreas into the portal vein in a pulsatile manner, and it is primarily supplied to hepatocytes. The liver is the first organ to receive insulin, and it clears most of the insulin during the first passage, which accounts for around 60–70% of the insulin. The lingering insulin enters the systemic circulation, where peripheral tissues such as muscles, adipose tissue, and kidneys utilize it moderately, and then the liver degrades it again during the second passage through the hepatic artery. Modified from [149].

Figure 5.

INSR structure, downstream signalling pathway, and function. Upon Upon binding to its cognate receptor, insulin triggers the phosphorylation and recruitment of key signalling mediators conducive to their activation, thereby enhancing cellular glucose uptake, and promoting glycogenesis. Abbreviations: AKT/PKB, protein kinase B (serine/threonine-specific protein kinase); GLUT, glucose transporter; MAPK, mitogen-activated protein kinase; mTORC2, mammalian target of rapamycin complex 2; PDK1, pyruvate dehydrogenase kinase 1; PH, pleckstrin homology; PI3K, phosphatidylinositol 3-kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; Rab, GTPase; RAC1, GTPase; S473, serine 473 residue; T308, threonine 308 residue.