Lipid Droplets in Disease

Lipid droplets (LDs) are a crucial part of lipid storage; thus, they are important players in a variety of diseases that are affected by lipid imbalances such as obesity, fatty liver disease, type 2 diabetes, Alzheimer's disease, cardiovascular disease, and cancer [...].

It is widely appreciated that LDs interact with other organelles including mitochondria [15]. Of relevance here is the beta-oxidation of fatty acids. Chokchaiwong and coworkers explore the genotype-phenotype relationship of electron-transfer flavoprotein dehydrogenase gene (ETFDH) with the pathogenesis of multiple acyl-CoA dehydrogenase deficiency (MADD) in mutated lympholastoid cells [16]. They found that MADD patients have increased LDs. Riboflavin and/or coenzyme Q10 supplementation rescues cells from this LD accumulation. Their results help clarify the molecular pathogenesis of MADD.
Understanding the role of LDs in disease provides pathways for treatment of obesity, NAFLD, and type 2 diabetes. Chen and coworkers explore the mechanisms of urodeoxycholic acid treatment, which has been shown to possess antioxidant and anti-inflammatory properties and also alleviates mitochondrial dysfunction and the progression of obesity-related diseases [17]. In this issue, they show that urodeoxycholic acid decreases LD number and size, reduced free fatty acid (FFA) and TAG levels, improved mitochondrial function, and enhanced white adipose tissue (WAT) browning in ob/ob mice. Importantly, they found that urodeoxycholic acid acts to reduce whole body adiposity.
LD presence in skeletal muscle is a hallmark of insulin resistance in type 2 diabetes mellitus. Paradoxically, trained athletes accumulate lipids in skeletal muscle and the size of their LDs in muscle tissue is positively correlated with insulin sensitivity. Li and coworkers review this phenomenon, which is called the athlete's paradox [18].
To understand how LD-bound lipase expression affects TAG homeostasis in human hepatocellular carcinoma (HCC) cells, Berndt and colleagues built a model, which shows that minor cell-to-cell variation in the expression level of these lipases can give rise to significant variations in LD size distributions [19]. In particular, they found that HCCs can be categorized into two groups based on their rate of free fatty acid uptake, phospholipid synthesis, and very low-density lipoprotein (VLDL) synthesis. Also, TAG accumulation in HCC did not correlate with the uptake rate of free fatty acids. These results point to important metabolic subpopulations of hepatocytes in HCC.
It is now being appreciated that lipid imbalance plays a major role in neurodegeneration such as in Alzheimer's disease. The E4 allele of APOE, whose gene product is a major structural component of low-density lipoproteins (LDLs), is a strong genetic risk factor for the development of late onset Alzheimer's disease [20]. Farmer and coworkers show that E4 expression in astrocytes results in an increase in small LDs compared to astrocytes expressing E3 [21]. PLIN2 levels were increased in the astrocytes expressing E4 over the E3-expressing cells. They also found that E4 astrocytes had decreased uptake of palmitate and decreased oxidation of exogenously supplied oleate and palmitate. Their work points to important links between the APOE gene and lipid metabolism in neurodegeneration. Lastly, Libbing and coworkers review the literature on the importance of LDs in host-pathogen interactions with a focus on bacteria [22]. The contributions to this issue show that LD formation, stability, and breakdown continue to be recognized as important players in a variety of diseases. In the next decade we will begin to see progress in the treatments of these diseases through LD-targeting strategies.

Conflicts of Interest:
The author declares no conflict of interest.