RESUMEN
Metabolic dysfunction-associated steatotic liver disease (MASLD) occurs in subjects with obesity and metabolic syndrome. MASLD may progress from simple steatosis (i.e., hepatic steatosis) to steatohepatitis, characterized by inflammatory changes and liver cell damage, substantially increasing mortality. Lifestyle measures associated with weight loss and/or appropriate diet help reduce liver fat accumulation, thereby potentially limiting progression to steatohepatitis. As for diet, both total energy and macronutrient composition significantly influence the liver's fat content. For example, the type of dietary fatty acids can affect the metabolism of lipids and hence their tissue accumulation, with saturated fatty acids having a greater ability to promote fat storage in the liver than polyunsaturated ones. In particular, polyunsaturated fatty acids of n-3 series (omega-3), such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), have been intensively studied for their antisteatotic effects, both in preclinical animal models of obesity and hepatic steatosis and in overweight/obese patients. Their effects may depend not only on the dose and duration of administration of omega-3, or DHA/EPA ratio, but also on the lipid class used for their supplementation. This review summarizes the available evidence from recent comparative studies using omega-3 supplementation via different lipid classes. Albeit the evidence is mainly limited to preclinical studies, it suggests that phospholipids and possibly wax esters could provide greater efficacy against MASLD compared to traditional chemical forms of omega-3 supplementation (i.e., triacylglycerols, ethyl esters). This cannot be attributed solely to improved EPA and/or DHA bioavailability, but other mechanisms may be involved. Keywords: MASLD ⢠Metabolic dysfunction-associated steatotic liver disease ⢠NAFLD ⢠Non-alcoholic fatty liver disease ⢠n-3 polyunsaturated fatty acids.
Asunto(s)
Suplementos Dietéticos , Ácidos Grasos Omega-3 , Hígado , Humanos , Animales , Ácidos Grasos Omega-3/administración & dosificación , Ácidos Grasos Omega-3/metabolismo , Ácidos Grasos Omega-3/uso terapéutico , Hígado/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Hígado Graso/metabolismo , Hígado Graso/tratamiento farmacológico , Metabolismo de los Lípidos/efectos de los fármacos , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/dietoterapia , Enfermedad del Hígado Graso no Alcohólico/patología , Obesidad/metabolismo , Obesidad/tratamiento farmacológico , Obesidad/dietoterapia , Obesidad/patologíaRESUMEN
OBJECTIVE: Resolution of low-grade inflammation of white adipose tissue (WAT) is one of the keys for amelioration of obesity-associated metabolic dysfunctions. We focused on the identification of adipokines, which could be involved at the early stages of resolution of WAT inflammation. METHODS AND PROCEDURE: Male C57BL/6J mice with obesity induced in response to a 22-week feeding corn oil-based high-fat (cHF) diet were divided into four groups and were fed with, for 2 weeks, control cHF diet or cHF-based diets supplemented with: (i) concentrate of n-3 long-chain polyunsaturated fatty acids, mainly eicosapentaenoic and docosahexaenoic acids (cHF+F); (ii) thiazolidinedione drug rosiglitazone (cHF+TZD); and (iii) both compounds (cHF+F+TZD). RESULTS: The short-term combined intervention exerted additive effect in the amelioration of WAT inflammation in obese mice, namely in the epididymal fat, even in the absence of any changes in either adipocyte volume or fat mass. The combined intervention elicited hypolipidaemic effect and induced adiponectin, whereas the responses to single interventions (cHF+F, cHF+TZD) were less pronounced. In addition, analysis in WAT lysates using protein arrays revealed that the levels of a small set of adipose tissue-related proteins, namely macrophage inflammatory protein 1γ, endoglin, vascular cell adhesion molecule 1 and interleukin 1 receptor antagonist, changed in response to the anti-inflammatory interventions and were strongly reduced in the cHF+F+TZD mice. These results were verified using both the analysis of gene expression and enzyme-linked immunosorbent analysis in WAT lysates. In contrast with adiponectin, which showed changing plasma levels in response to dietary interventions, the levels of the above proteins were affected only in WAT. CONCLUSIONS: We identified several adipose tissue-related proteins, which are locally involved in resolution of low-grade inflammation and remodelling of WAT.
Asunto(s)
Tejido Adiposo Blanco/metabolismo , Tejido Adiposo Blanco/patología , Ácidos Docosahexaenoicos/farmacología , Ácidos Grasos Omega-3/farmacología , Inflamación/patología , Obesidad/patología , Tiazolidinedionas/farmacología , Adipocitos/metabolismo , Adipoquinas/metabolismo , Animales , Dieta Alta en Grasa , Grasas de la Dieta , Metabolismo Energético , Ensayo de Inmunoadsorción Enzimática , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Obesidad/inmunología , Reacción en Cadena en Tiempo Real de la Polimerasa , RosiglitazonaRESUMEN
AIMS/HYPOTHESIS: Diets rich in n-3 polyunsaturated fatty acids, namely eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), protect against insulin resistance and obesity in rodents and increase insulin sensitivity in healthy humans. We tested whether the anti-diabetic effects of EPA and DHA involve enhanced production of the endogenous insulin sensitiser, adiponectin. METHODS: We studied the effects, in an obesity-promoting high-fat diet, of partial replacement of vegetable oils by EPA/DHA concentrate (6% EPA, 51% DHA) over a 5-week period in adult male C57BL/6J mice that either had free access to food or had their food intake restricted by 30%. At the end of the treatment, systemic markers of lipid and glucose metabolism and full-length adiponectin and leptin were measured. Adiponectin (Adipoq) and leptin (Lep) gene expression in dorsolumbar and epididymal white adipose tissue (WAT) and isolated adipocytes was quantified and adipokine production from WAT explants evaluated. RESULTS: In mice with free access to food, plasma triacylglycerols, NEFA, and insulin levels were lower in the presence of EPA/DHA, while glucose and leptin levels were not significantly altered. Food restriction decreased plasma triacylglycerols, glucose, insulin and leptin, but not adiponectin. EPA/DHA increased plasma adiponectin levels, independent of food intake, reflecting the stimulation of Adipoq expression in adipocytes and the release of adiponectin from WAT, particularly from epididymal fat. Expression of Lep and the release of leptin from WAT, while being extremely sensitive to caloric restriction, was unaltered by EPA/DHA. CONCLUSIONS/INTERPRETATION: Intake of diets rich in EPA and DHA leads to elevated systemic concentrations of adiponectin, largely independent of food intake or adiposity and explain, to some extent, their anti-diabetic effects.
Asunto(s)
Adiponectina/biosíntesis , Adiponectina/genética , Grasas de la Dieta/farmacología , Ácidos Docosahexaenoicos/farmacología , Ácido Eicosapentaenoico/farmacología , Quinasas de la Proteína-Quinasa Activada por el AMP , Adipocitos/química , Adipocitos/metabolismo , Adiponectina/sangre , Tejido Adiposo/química , Tejido Adiposo/metabolismo , Animales , Composición Corporal , Restricción Calórica , Grasas de la Dieta/administración & dosificación , Ácidos Docosahexaenoicos/administración & dosificación , Ingestión de Alimentos , Ácido Eicosapentaenoico/administración & dosificación , Activación Enzimática , Regulación de la Expresión Génica , Glucosa/metabolismo , Insulina/sangre , Insulina/fisiología , Resistencia a la Insulina , Leptina/análisis , Leptina/sangre , Leptina/genética , Leptina/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/fisiopatología , Obesidad/prevención & control , Proteínas Quinasas/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Triglicéridos/sangreRESUMEN
AIMS/HYPOTHESIS: Intake of n-3 polyunsaturated fatty acids reduces adipose tissue mass, preferentially in the abdomen. The more pronounced effect of marine-derived eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids on adiposity, compared with their precursor alpha-linolenic acid, may be mediated by changes in gene expression and metabolism in white fat. METHODS: The effects of EPA/DHA concentrate (6% EPA, 51% DHA) admixed to form two types of high-fat diet were studied in C57BL/6J mice. Oligonucleotide microarrays, cDNA PCR subtraction and quantitative real-time RT-PCR were used to characterise gene expression. Mitochondrial proteins were quantified using immunoblots. Fatty acid oxidation and synthesis were measured in adipose tissue fragments. RESULTS: Expression screens revealed upregulation of genes for mitochondrial proteins, predominantly in epididymal fat when EPA/DHA concentrate was admixed to a semisynthetic high-fat diet rich in alpha-linolenic acid. This was associated with a three-fold stimulation of the expression of genes encoding regulatory factors for mitochondrial biogenesis and oxidative metabolism (peroxisome proliferator-activated receptor gamma coactivator 1 alpha [Ppargc1a, also known as Pgc1alpha] and nuclear respiratory factor-1 [Nrf1] respectively). Expression of genes for carnitine palmitoyltransferase 1A and fatty acid oxidation was increased in epididymal but not subcutaneous fat. In the former depot, lipogenesis was depressed. Similar changes in adipose gene expression were detected after replacement of as little as 15% of lipids in the composite high-fat diet with EPA/DHA concentrate, while the development of obesity was reduced. The expression of Ppargc1a and Nrf1 was also stimulated by n-3 polyunsaturated fatty acids in 3T3-L1 cells. CONCLUSIONS/INTERPRETATION: The anti-adipogenic effect of EPA/DHA may involve a metabolic switch in adipocytes that includes enhancement of beta-oxidation and upregulation of mitochondrial biogenesis.