Cardiomyocyte Regulation of Systemic Lipid Metabolism by the Apolipoprotein B-Containing Lipoproteins in Drosophila

Abstract

The heart has emerged as an important organ in the regulation of systemic lipid homeostasis; however, the underlying mechanism remains poorly understood. Here, we show that Drosophila cardiomyocytes regulate systemic lipid metabolism by producing apolipoprotein B-containing lipoproteins (apoB-lipoproteins), essential lipid carriers that are so far known to be generated only in the fat body. In a Drosophila genetic screen, we discovered that when haplo-insufficient, microsomal triglyceride transfer protein (mtp), required for the biosynthesis of apoB-lipoproteins, suppressed the development of diet-induced obesity. Tissue-specific inhibition of Mtp revealed that whereas knockdown of mtp only in the fat body decreases systemic triglyceride (TG) content on normal food diet (NFD) as expected, knockdown of mtp only in the cardiomyocytes also equally decreases systemic TG content on NFD, suggesting that the cardiomyocyte- and fat body-derived apoB-lipoproteins serve similarly important roles in regulating whole-body lipid metabolism. Unexpectedly, on high fat diet (HFD), knockdown of mtp in the cardiomyocytes, but not in fat body, protects against the gain in systemic TG levels. We further showed that inhibition of the Drosophila apoB homologue, apolipophorin or apoLpp, another gene essential for apoB-lipoprotein biosynthesis, affects systemic TG levels similarly to that of Mtp inhibition in the cardiomyocytes on NFD or HFD. Finally, we determined that HFD differentially alters Mtp and apoLpp expression in the cardiomyocytes versus the fat body, culminating in higher Mtp and apoLpp levels in the cardiomyocytes than in fat body and possibly underlying the predominant role of cardiomyocyte-derived apoB-lipoproteins in lipid metabolic regulation. Our findings reveal a novel and significant function of heart-mediated apoB-lipoproteins in controlling lipid homeostasis.

Suppression of store-operated calcium entry causes dilated cardiomyopathy of the Drosophila heart

“…2J-R). It is possible that 4xhand-GAL4 does not drive RNAi expression as strongly in the larval heart as does tinC-GAL4, as has previously been noted (Lee et al, 2017), thus explaining the weaker effects of 4xhand-GAL4 driven Stim and Orai RNAi on larval heart contractility. Because of this, the 4xhand-GAL4 driver was not used for further larval heart analysis.…”

Triacylglycerol Metabolism in Drosophila melanogaster

“…Although the midgut is the dedicated site of lipid absorption, de novo synthesis, and export to the circulatory system, it lacks the capacity to synthesize lipoproteins, but relies on lipoprotein secretion from other tissues, principally the fat body (Palm et al 2012). However, recent data suggest that, in response to nutritional challenges such as high fat levels, cardiac muscle cells deliver an additional pool of Lpp to the hemolymph (Lee et al 2017).…”

Drosophilaas a model to study obesity and metabolic disease

“…For high-carbohydrate feeding, high-sucrose diets are the most common (Buescher et al, 2013;Garrido et al, 2015;Havula et al, 2013;Navrotskaya et al, 2016;Musselman et al, 2011;Pasco and Léopold, 2012;Reis, 2016;Rovenko et al, 2015a); however, highglucose and high-fructose diets have also been used (Rovenko et al, 2015b). For high-fat feeding, coconut oil supplementation is the most common way to elicit diet-induced obesity in flies (Birse et al, 2010;Heinrichsen et al, 2014;Hong et al, 2016;Reed et al, 2010), although lard and the hydrogenated soybean and palm oil product known as Crisco have also been used (Lee et al, 2017;Musselman et al, 2011;Woodcock et al, 2015). The formulation of these diets can be tricky and care must be taken to avoid reduced survival owing to unusually sticky or dry food conditions.…”

“…Finally, the heart itself can control circulating and stored lipids in a non-autonomous manner via the regulation of lipoprotein metabolism. Cardiomyocyte-specific knockdown of the microsomal triglyceride transfer protein or its target lipoprotein, Lpp, prevents fat body TAG accumulation during high-fat diet-induced obesity (Lee et al, 2017).…”