Hepatic n-3 Polyunsaturated Fatty Acid Depletion Promotes Steatosis and Insulin Resistance in Mice: Genomic Analysis of Cellular Targets

Abstract

Patients with non-alcoholic fatty liver disease are characterised by a decreased n-3/n-6 polyunsaturated fatty acid (PUFA) ratio in hepatic phospholipids. The metabolic consequences of n-3 PUFA depletion in the liver are poorly understood. We have reproduced a drastic drop in n-3 PUFA among hepatic phospholipids by feeding C57Bl/6J mice for 3 months with an n-3 PUFA depleted diet (DEF) versus a control diet (CT), which only differed in the PUFA content. DEF mice exhibited hepatic insulin resistance (assessed by euglycemic-hyperinsulinemic clamp) and steatosis that was associated with a decrease in fatty acid oxidation and occurred despite a higher capacity for triglyceride secretion. Microarray and qPCR analysis of the liver tissue revealed higher expression of all the enzymes involved in lipogenesis in DEF mice compared to CT mice, as well as increased expression and activation of sterol regulatory element binding protein-1c (SREBP-1c). Our data suggest that the activation of the liver X receptor pathway is involved in the overexpression of SREBP-1c, and this phenomenon cannot be attributed to insulin or to endoplasmic reticulum stress responses. In conclusion, n-3 PUFA depletion in liver phospholipids leads to activation of SREBP-1c and lipogenesis, which contributes to hepatic steatosis.

Both maternal and offspring Elovl2 genotypes determine systemic DHA levels in perinatal mice

“…Moreover, the offspring of mothers maintained on a DHAenriched diet showed a significant downregulation of the classical lipogenic transcription factor, Srebp-1c, and its target genes, Fas and Scd1 (Fig. 7A-C), which supports the concept of DHA as a suppressor of lipogenesis described previously in adult animals (25)(26)(27). Because our data suggests that the DHA level in the offspring is a result of a dynamic interplay between hepatic (supplemental Fig.…”

Energy restriction does not prevent insulin resistance but does prevent liver steatosis in aging rats on a Western-style diet

“…The fructose component of sucrose increases hepatic de novo lipogenesis and TG synthesis [36,37] and, thus may have exacerbated the age-related TG accumulation observed in liver [38], skeletal muscle [39], and plasma [39,40]. In plasma, higher plasma TC and cholesteryl ester concentrations in 19 AL rats are probably associated with the increase in hepatic cholesterol synthesis and reduced clearance of plasma low-density lipoprotein observed during aging [41,42] and u-3 PUFA deficiency [43]. Fish oil enriched in u-3…”

Omega-3 fatty acid supplementation and cardiovascular disease

“…Dietary C 20-22 3 PUFA are feedback inhibitors of endogenous C 20-22 3 and 6 PUFA synthesis, as well as robust inhibitors of DNL ( 66 ). Recent studies by Pachikian et al ( 76 ) establish the impact of dietary 3 PUFA on wholebody metabolism. In this study, all 3 PUFA were removed from the diet, but 6 PUFA were maintained at essential fatty acid-suffi cient levels.…”