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. 2018 Feb 5;11(2):dmm032086.
doi: 10.1242/dmm.032086.

Inhibition of galectin-3 Ameliorates the Consequences of Cardiac Lipotoxicity in a Rat Model of Diet-Induced Obesity

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Free PMC article

Inhibition of galectin-3 Ameliorates the Consequences of Cardiac Lipotoxicity in a Rat Model of Diet-Induced Obesity

Gema Marín-Royo et al. Dis Model Mech. .
Free PMC article

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.

Keywords: Galectin-3; Insulin resistance; Lipotoxicity; Mitochondria; Obesity; Oxidative stress.

Conflict of interest statement

Competing interestsThe authors declare no competing or financial interests.

Figures

Fig. 1.
Fig. 1.
Impact of Gal-3 inhibition on cardiac 18F-FDG-uptake and the HOMA index in obese rats. (A) Representative photographs of 18F-Fluorodeoxyglucose (FDG) PET/CT scans of the heart from rats fed a standard diet (CT) or a high fat diet (HFD) treated with vehicle or with MCP, the inhibitor of Gal-3 activity (100 mg/kg/day) in coronal, sagittal and trans-axial views scaled to SUV. (B) Quantification in SUV units. (C) HOMA index of the different experimental groups. Bar graphs represent the mean± s.e.m. of 6-8 animals. *P<0.05; **P<0.01 control group.
Fig. 2.
Fig. 2.
Effects of Gal-3 inhibition on lipid species in heart from control and obese rats. Rats were fed a standard diet (CT) or a high fat diet (HFD) and treated with control vehicle or with the Gal-3 activity inhibitor MCP (100 mg/kg/day). Cardiac levels of (A) total TGs, (B) the three main types of TG, (C) ceramide (Cer), (D) total sphingomyelins (SM), (E) total lyso phosphatidylcholine (LPC), (F) the three main types of LPC. Bar graphs represent the mean±s.e.m. of 6-8 animals.*P<0.05; **P<0.01; ***P<0.001 vs control group. P<0.05; ††P<0.01; †††P<0.001 vs HFD group.
Fig. 3.
Fig. 3.
Impact of Gal-3 inhibition on proteins and superoxide anion production in hearts from control and obese rats. Hearts from rats fed a standard diet (CT) or a high fat diet (HFD) treated with vehicle or with the inhibitor of Gal-3 activity (modified citrus pectin; MCP; 100 mg/kg/day) were analyzed. Protein expression of (A) carnitine palmitoyl transferase IA (CPT1A), (B) mitofusin 1 (MFN1), (D) for mitochondrial complexes I (subunit NDUFB8), II (30 kDa) and V (alpha subunit) are presented. (C) Representative microphotographs (magnification ×40) of cardiac sections labeled with MitoSOX and quantification of superoxide anions in heart. Bar graphs represent the mean±s.e.m. of 6-8 animals normalized to porin. Scale bars: 50 µm. *P<0.05; **P<0.01 vs control group. P<0.05; ††P<0.01 vs HFD group.
Fig. 4.
Fig. 4.
Effects of Gal-3 inhibition on mitochondrial function, glycolysis, membrane potential, ROS production and β-oxidation in palmitic-acid-treated H9c2 cells. (A) Basal respiration expressed as oxygen consumption rate (OCR). (B) Basal glycolysis expressed as extracellular acidification rate (ECAR). (C) Proton leak respiration expressed as OCR. (D) Quantification of flow cytometry analysis of mitochondrial membrane potential in cells stained with Rhodamine 123 expressed as mean fluorescence intensity (MFI). (E) Quantification of flow cytometry analysis of mitochondrial superoxide anions in cells labeled with MitoSOX expressed as MFI, (F) Quantification of β-oxidation in cardiac myoblasts treated for 24 h with palmitic acid (200 µmol/l) in the presence of absence inhibitor of Gal-3 activity (modified citrus pectin; MCP; 0.01%). Error bars represent the mean±s.e.m. of four assays. **P<0.01; ***P<0.001 vs vehicle-treated cells (CT).

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