Extra virgin olive oil improved body weight and insulin sensitivity in high fat diet-induced obese LDLr−/−.Leiden mice without attenuation of steatohepatitis

Abstract

Dietary fatty acids play a role in the pathogenesis of obesity-associated non-alcoholic fatty liver disease (NAFLD), which is associated with insulin resistance (IR). Fatty acid composition is critical for IR and subsequent NAFLD development. Extra-virgin olive oil (EVOO) is the main source of monounsaturated fatty acids (MUFA) in Mediterranean diets. This study examined whether EVOO-containing high fat diets may prevent diet-induced NAFLD using Ldlr−/−. Leiden mice. In female Ldlr−/−.Leiden mice, the effects of the following high fat diets (HFDs) were examined: a lard-based HFD (HFD-L); an EVOO-based HFD (HFD-EVOO); a phenolic compounds-rich EVOO HFD (HFD-OL). We studied changes in body weight (BW), lipid profile, transaminases, glucose homeostasis, liver pathology and transcriptome. Both EVOO diets reduced body weight (BW) and improved insulin sensitivity. The EVOOs did not improve transaminase values and increased LDL-cholesterol and liver collagen content. EVOOs and HFD-L groups had comparable liver steatosis. The profibrotic effects were substantiated by an up-regulation of gene transcripts related to glutathione metabolism, chemokine signaling and NF-kappa-B activation and down-regulation of genes relevant for fatty acid metabolism. Collectivelly, EVOO intake improved weight gain and insulin sensitivity but not liver inflammation and fibrosis, which was supported by changes in hepatic genes expression.

Therapeutic Properties and Use of Extra Virgin Olive Oil in Clinical Nutrition: A Narrative Review and Literature Update

“…In people with type 1 diabetes mellitus (DM1), EVOO has been associated with an improvement in weight, waist circumference [ 186 ], lipid profile [ 187 ], and quality of life [ 188 ]. Lastly, polyphenol-rich EVOO has maintained insulin secretion and insulin sensitivity during a high-fat diet in animal models [ 189 ].…”

“…Oleuropein and hydroxytyrosol can reduce adipocyte hyperplasia and hypertrophy, by inhibition of adipogenesis-related genes in human cell lines [ 305 , 306 ] and stimulation of mitochondrial biogenesis-related genes in murine adipocytes [ 307 ]. When fed high-fat diets, EVOO-supplemented mice underwent lower weight gains [ 189 ], and they showed less metabolic, inflammatory, and microbiota disruption [ 308 ], as well as more modest subcutaneous and visceral fat development—in relation to a higher basal energy expenditure proportional to their weight—which could be explained by a higher expression of Ucp genes in muscle and visceral fat [ 309 ]. Regarding BMI reduction, a meta-analysis of clinical trials calculated statistically significant improvements for food enrichment with phytosterols and phytostanols in dyslipidemic, overweight, and obese subjects [ 310 ].…”

“…In humans, levels of sitosterols in the liver in adults with NAFLD have shown an inverse correlation with the degree of steatosis and lobular inflammation by liver biopsy [ 311 ] In animal models, liver damage induced by a high-fat diet was significantly reduced by supplementation with EVOO [ 312 , 313 ], EPA + DHA [ 314 , 315 , 316 ], DHA + EVOO [ 317 ] EPA + hydroxytyrosol [ 318 , 319 , 320 , 321 ], or hydroxytyrosol [ 322 ], showing beneficial effects on inflammation, lipid content, and hepatocyte gene expression. This evidence is mixed, as other animal models have not demonstrated a positive effect of EVOO and its phenolic compounds on the development of NAFLD [ 189 ] or its regression [ 323 ]. The beneficial effect of EVOO against NAFLD could be explained by mitochondrial protection—preventing the decrease in nitrated fatty-acid levels caused by a high-fat diet [ 324 ]—this ability being directly related to its phenolic content [ 325 ].…”

White Button Mushroom Extracts Modulate Hepatic Fibrosis Progression, Inflammation, and Oxidative Stress In Vitro and in LDLR-/- Mice

“…The overproduction of oxidative species induces the inflammatory response [61], and this response is accompanied by a reduction in antioxidant capacity [62], which promotes the activation of HSCs and liver damage. Other studies suggested a higher gene expression of antioxidant enzymes in response to a liver ROS overproduction, in order to counteract the oxidative stress [63,64]. Besides, oxidative stress-induced hepatic damage is also affected by imbalance of other enzymes, such as iNOS, whose gene levels are highly expressed in HFD-induced NASH models [65].…”

Target Deconvolution of Fenofibrate in Nonalcoholic Fatty Liver Disease Using Bioinformatics Analysis

“…It plays a crucial function in the clearance of cholesterol by the liver [ 119 ]. LDLR deficient rodents have been used to establish models of NAFLD [ 120 , 121 ]. In those models, elevations in hepatic neutral and hepatic proinflammatory oxylipins were observed [ 122 ].…”