Inhibition of galectin-3 ameliorates the consequences of cardiac lipotoxicity in a rat model of diet-induced obesity

Abstract

Obesity is accompanied by metabolic alterations characterized by insulin resistance and cardiac lipotoxicity. Galectin-3 (Gal-3) induces cardiac inflammation and fibrosis in the context of obesity; however, its role in the metabolic consequences of obesity is not totally established. We have investigated the potential role of Gal-3 in the cardiac metabolic disturbances associated with obesity. In addition, we have explored whether this participation is, at least partially, acting on mitochondrial damage. Gal-3 inhibition in rats that were fed a high-fat diet (HFD) for 6 weeks with modified citrus pectin (MCP; 100 mg/kg/day) attenuated the increase in cardiac levels of total triglyceride (TG). MCP treatment also prevented the increase in cardiac protein levels of carnitine palmitoyl transferase IA, mitofusin 1, and mitochondrial complexes I and II, reactive oxygen species accumulation and decrease in those of complex V but did not affect the reduction in 18F-fluorodeoxyglucose uptake observed in HFD rats. The exposure of cardiac myoblasts (H9c2) to palmitic acid increased the rate of respiration, mainly due to an increase in the proton leak, glycolysis, oxidative stress, β-oxidation and reduced mitochondrial membrane potential. Inhibition of Gal-3 activity was unable to affect these changes. Our findings indicate that Gal-3 inhibition attenuates some of the consequences of cardiac lipotoxicity induced by a HFD since it reduced TG and lysophosphatidyl choline (LPC) levels. These reductions were accompanied by amelioration of the mitochondrial damage observed in HFD rats, although no improvement was observed regarding insulin resistance. These findings increase the interest for Gal-3 as a potential new target for therapeutic intervention to prevent obesity-associated cardiac lipotoxicity and subsequent mitochondrial dysfunction.

The Crosstalk between Cardiac Lipotoxicity and Mitochondrial Oxidative Stress in the Cardiac Alterations in Diet-Induced Obesity in Rats

“…Ceramides are not only essential structural components of cell membranes, but also function as second messenger molecules in cell signaling, and have been implicated in different pathological settings [31][32][33]. The present data confirm previous observations, which support a negative effect of ceramides in insulin signaling in different tissues [16,33,34]. In addition, our data supports a role for ceramides in myocardial fibrosis, as well as hypertrophy.…”

“…In fact, a correlation was found between mitochondrial TG levels and those of these proteins. Similar increases have been found and were associated with high cardiac lipid content, not only in the context of obesity, but also in that of diabetes and myocardial ischemia [5,16,24].…”

“…Methanol:chloroform (1:2) cardiac extracts were evaporated to dryness and the pellet resuspended in 250 µL of acetone:2-propanol:ethanol (3:4:3) and used for triglyceride (TG) measurement, as previously reported [5]. Another aliquot was evaporated to dryness and the pellet resuspended in 200 µL methanol:water (9:1) and used for phospholipid (PPLs) measurement as previously reported [16]. Extracts were kept at −80 • C until analysis.…”

Galectin-3 Is a Potential Mediator for Atherosclerosis

“…Moreover, the effect of Gal-3 on cardiac metabolic disturbance associated with obesity has been investigated. Marín-Royo et al found that Gal-3 inhibition attenuated the consequences of cardiac lipotoxicity induced by high-fat diet in vivo [16]. Therefore, Gal-3 might exacerbate atherosclerosis plaque through promoting endocytosis of lipoprotein and disturbing lipid metabolism.…”

“…As an important inflammatory biomarker, Gal-3 can promote the secretion of other proinflammatory factors like tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) through activation of macrophages in a dose-dependent manner [15]. Gal-3 also participates in the progression of lipid endocytosis, cell apoptosis, cell differentiation, cell adhesion, and tumor metastasis [16][17][18].…”