Biogenesis and Breakdown of Lipid Droplets in Pathological Conditions

Abstract

Lipid droplets (LD) have long been considered as mere fat drops; however, LD have lately been revealed to be ubiquitous, dynamic and to be present in diverse organelles in which they have a wide range of key functions. Although incompletely understood, the biogenesis of eukaryotic LD initiates with the synthesis of neutral lipids (NL) by enzymes located in the endoplasmic reticulum (ER). The accumulation of NL leads to their segregation into nanometric nuclei which then grow into lenses between the ER leaflets as they are further filled with NL. The lipid composition and interfacial tensions of both ER and the lenses modulate their shape which, together with specific ER proteins, determine the proneness of LD to bud from the ER toward the cytoplasm. The most important function of LD is the buffering of energy. But far beyond this, LD are actively integrated into physiological processes, such as lipid metabolism, control of protein homeostasis, sequestration of toxic lipid metabolic intermediates, protection from stress, and proliferation of tumours. Besides, LD may serve as platforms for pathogen replication and defense. To accomplish these functions, from biogenesis to breakdown, eukaryotic LD have developed mechanisms to travel within the cytoplasm and to establish contact with other organelles. When nutrient deprivation occurs, LD undergo breakdown (lipolysis), which begins with the LD-associated members of the perilipins family PLIN2 and PLIN3 chaperone-mediated autophagy degradation (CMA), a specific type of autophagy that selectively degrades a subset of cytosolic proteins in lysosomes. Indeed, PLINs CMA degradation is a prerequisite for further true lipolysis, which occurs via cytosolic lipases or by lysosome luminal lipases when autophagosomes engulf portions of LD and target them to lysosomes. LD play a crucial role in several pathophysiological processes. Increased accumulation of LD in non-adipose cells is commonly observed in numerous infectious diseases caused by intracellular pathogens including viral, bacterial, and parasite infections, and is gradually recognized as a prominent characteristic in a variety of cancers. This review discusses current evidence related to the modulation of LD biogenesis and breakdown caused by intracellular pathogens and cancer.

Cancer metabolic features allow discrimination of tumor from white blood cells by label-free multimodal optical imaging

“…However, they did not study the specific glucose uptake activity in cancer and WBCs. Herein, we observed a very low Raman signal in the spectral region around 2,120 cm −1 for WBCs, that indeed showed lower rate of LDs production ( Melo and Weller, 2016 ; Weller, 2016 ; Fader Kaiser et al, 2022 ).…”

“…This is in line with previously reported studies assessing that cancer cells contain abundant lipid droplets functioning as reservoirs of energy and molecular components to support cancer development ( Hyun et al, 2016 ; Melo and Weller, 2016 ; Geng and Guo, 2017 ; Jin and Yuan, 2020 ). LDs have been previously proposed as cancer biomarkers and LD-associate proteins are overexpressed in most if not all cancer cells including colorectal, lung, skin, breast, prostate, hepatic, renal, brain, ovarian and cervical ( Cruz et al, 2020 ; Fader Kaiser et al, 2022 ). In contrast, we find that WBCs are appeared to be the least efficient LD producer among all the tested cell types.…”

“…In contrast, we find that WBCs are appeared to be the least efficient LD producer among all the tested cell types. WBCs contain few small, nearly undetectable LDs (1-5 LDs/cells) and even if during pathogen invasion or allergic response some class of WBCs can accumulate more LDs, the amount, size and composition of these remain very different from those of cancer cells ( Koizume and Miyagi, 2016 ; Weller, 2016 ; Onal et al, 2017 ; Fader Kaiser et al, 2022 ). Therefore, the LD abundance in cancer cells represents a general parameter that can be used for efficiently discriminating cancer from blood cells ( Cruz et al, 2020 ).…”

Characterization of lipid droplet metabolism patterns identified prognosis and tumor microenvironment infiltration in gastric cancer

“…A study has constructed a risk prediction scoring model based on genes related to lipid metabolism, which can effectively predict the prognosis of patients ( 51 ). Lipid droplets are an important energy reservoir for cancer cells and accumulation of lipid droplets can be found in many cancer cells ( 52 – 55 ). Several studies have shown that autophagy and lipid droplet synthesis are closely related and that it can promote lipid droplet synthesis to increase the resistance of cancer cells to stress, thus promoting cancer cell progression ( 56 ).…”

Ceramide Acyl Chain Length and Its Relevance to Intracellular Lipid Regulation

“…The formation of LD occurs at the ER and begins with the accumulation of triglycerides between the ER membranes, and the subsequent curving and formation of an oil lens. With sufficient accumulation of triglycerides, the oil lens will then bud off from the ER as LD [ 87 ]. LD biogenesis involves many proteins, but three ER proteins—seipin, perilipin, and FITM2—are critical for LD formation.…”