Lipoatrophy‐Associated Insulin Resistance and Hepatic Steatosis are Attenuated by Intake of Diet Rich in Omega 3 Fatty Acids

Abstract

Scope: Glucose homeostasis and progression of nonalcoholic fatty liver disease (NAFLD) and hepatomegaly in severe lipoatrophic mice and their modulation by intake of a diet rich in omega 3 (n-3) fatty acids (HFO) are evaluated. Methods and results: Severe lipoatrophic mice induced by PPAR-deletion exclusively in adipocytes (A-PPAR KO) and littermate controls (A-PPAR WT)are evaluated for glucose homeostasis and liver mass, proteomics, lipidomics, inflammation, and fibrosis. Lipoatrophic mice are heavier than controls, severely glucose intolerant, and hyperinsulinemic, and develop NAFLD characterized by increased liver glycogen, triacylglycerol, and diacylglycerol contents, mitotic index, apoptosis, inflammation, steatosis score, fibrosis, and fatty acid synthase (FAS) content and activity. Lipoatrophic mice also display liver enrichment with monounsaturated in detriment of polyunsaturated fatty acids including n-3 fatty acids, and increased content of cardiolipin, a tetracyl phospholipid exclusively found at the mitochondria inner membrane. Administration of a high-fat diet rich in n-3 fatty acids (HFO) to lipoatrophic mice enriches liver with n-3 fatty acids, reduces hepatic steatosis, FAS content and activity, apoptosis, inflammation, and improves glucose homeostasis. Conclusion: Diet enrichment with n-3 fatty acids improves glucose homeostasis and reduces liver steatosis and inflammation without affecting hepatomegaly in severe lipoatrophic mice.

Vitamin D3 enhances the effects of omega‐3 oils against metabolic dysfunction‐associated fatty liver disease in rat

“…Concomitantly, the hepatic concentrations of adiponectin alongside the antioxidants and anti-inflammatory markers increased significantly, while leptin with the pro-inflammatory and pro-oxidative stress molecules diminished in the VD and OM groups than the PC group. Our results are aligned with many reports that have advocated the potential therapeutic values of VD 3 [26][27][28][48][49][50] and omega-3 oils 17,[21][22][23][24][25] against MAFLD, plausibly by enhancing insulin sensitivity, reducing lipogenesis alongside antioxidative and antiinflammatory actions. Nevertheless, the OM group disclosed lower body weight with enhanced hepatoprotective effects than the VD group.…”

“…Although VD 3 also attenuated liver steatosis, deregulations of adipokines, inflammation, and oxidative stress in MAFLD patients, 48–50 other randomized clinical trials (RCTs) failed to detect significant beneficial anti‐steatotic effects for the hormone 51,52 . On the other hand, omega‐3 oils also abated MAFLD in murine by lowering insulin resistance, lipogenesis, inflammation, oxidative stress, and apoptosis 17,21,22 . Likewise, RCTs have reported reductions in intrahepatic triglycerides with improvements in liver stiffness, liver enzymes, and lipid profile following omega‐3 oils supplementation in MAFLD patients 23–25 …”

“…51,52 On the other hand, omega-3 oils also abated MAFLD in murine by lowering insulin resistance, lipogenesis, inflammation, oxidative stress, and apoptosis . 17,21,22 Likewise, RCTs have reported reductions in intrahepatic triglycerides with improvements in liver stiffness, liver enzymes, and lipid profile following omega-3 oils supplementation in MAFLD patients. [23][24][25] Our findings revealed that both monotherapies markedly reduced obesity, FBG, insulin, HOMA-IR, triglycerides, total cholesterol, and LDL with concurrent increases in HDL and total protein relative to the PC group.…”

“…Hence, many research groups have been questing for safe and effective remedies for MAFLD that could concomitantly improve the associated metabolic disorders, intrahepatic lipid deposition, oxidative stress, and inflammation 19,20 . In this regard, omega‐3 oils are polyunsaturated fatty acids, which are abundantly found in marine nutritional sources, have potent antilipidemic, hypoglycemic, antioxidative, and anti‐inflammatory actions 17,21,22 . Additionally, many clinical studies have reported that omega‐3 oils improved MAFLD by modulating several lipid metabolic pathways and suppressing oxidative stress and inflammation in hepatic tissues 23–25 .…”

“…19,20 In this regard, omega-3 oils are polyunsaturated fatty acids, which are abundantly found in marine nutritional sources, have potent antilipidemic, hypoglycemic, antioxidative, and anti-inflammatory actions. 17,21,22 Additionally, many clinical studies have reported that omega-3 oils improved MAFLD by modulating several lipid metabolic pathways and suppressing oxidative stress and inflammation in hepatic tissues. [23][24][25] Similarly, vitamin D 3 (VD 3 ) is a plethoric steroid hormone that robustly inhibits oxidative stress and inflammation alongside regulating glucose and lipid metabolism.…”