c9,t11-Conjugated linoleic acid ameliorates steatosis by modulating mitochondrial uncoupling and Nrf2 pathway

Abstract

Oxidative stress, hepatic steatosis, and mitochondrial dysfunction are key pathophysiological features of nonalcoholic fatty liver disease. A conjugated linoleic acid (CLA) mixture of cis9,trans11 (9,11-CLA) and trans10,cis12 (10,12-CLA) isomers enhanced the antioxidant/detoxifying mechanism via the activation of nuclear factor E2-related factor-2 (Nrf2) and improved mitochondrial function, but less is known about the actions of specific isomers. The differential ability of individual CLA isomers to modulate these pathways was explored in Wistar rats fed for 4 weeks with a lard-based high-fat diet (L) or with control diet (CD), and, within each dietary treatment, two subgroups were daily administered with 9,11-CLA or 10,12-CLA (30 mg/day). The 9,11-CLA, but not 10,12-CLA, supplementation to CD rats improves the GSH/GSSG ratio in the liver, mitochondrial functions, and Nrf2 activity. Histological examination reveals a reduction of steatosis in L-fed rats supplemented with both CLA isomers, but 9,11-CLA downregulated plasma concentrations of proinflammatory markers, mitochondrial dysfunction, and oxidative stress markers in liver more efficiently than in 10,12-CLA treatment. The present study demonstrates the higher protective effect of 9,11-CLA against diet-induced pro-oxidant and proinflammatory signs and suggests that these effects are determined, at least in part, by its ability to activate the Nrf2 pathway and to improve the mitochondrial functioning and biogenesis

Conjugated Linoleic Acid (CLA) Stimulates Mitochondrial Biogenesis Signaling by the Upregulation of PPARγ Coactivator 1α (PGC‐1α) in C2C12 Cells

“…Our results suggest that the c9,t11 isomer increased expression of cytochrome c, while t10,c12 isomer increased expression of VDAC. The former observation is consistent with Mollica et al [42] that the c9,t11 isomer, but not the t10,c12 isomer, induced higher cytochrome c activity in Wistar rats. There are currently no reports of CLA's effect on VDAC, however, it was reported that other polyunsaturated fatty acids, DHA and eicosapentaenoic acid (EPA), did not increase VDAC expression in male Wistar rats [43].…”

Conjugated linoleic acid prevents age-dependent neurodegeneration in a mouse model of neuropsychiatric lupus via the activation of an adaptive response

“…The presented data suggest that the beneficial activity of CLA is mediated at least in part by its ability to improve systemic antioxidant and detoxifying defenses via the activation of the Nrf2 pathway. Moreover, on the basis of our previous studies indicating the ability of the cis 9 trans 11 CLA to activate this pathway (17,18), it can be inferred that this isomer may be responsible for the neuroprotective activity of the CLA mixture. Further research is currently in progress to confirm this hypothesis.…”

“…Such activation of this defensive mechanism by CLA, characterized by a hormetic/ biphasic dose-response pattern (i.e., low-dose stimulation and high-dose inhibition), is not completely unexpected, and it is shared by n-3 PUFAs (DHA and EPA) (16,45). Moreover, the ability of CLA and PUFA to trigger Nrf2 activity (16)(17)(18)46), as well as their pro-oxidant (23,47) and antioxidant effects (45,48), are consistent with the hormetic effects of ROS on Nrf2 pathways (9).…”

“…Most Nrf2 activators are vegetable/spice constituents (15), whereas only two types of fatty acids contained in foods of animal origin exhibited such ability: the n-3 PUFAs (DHA and EPA) (16) and the cis 9 , trans 11 isomer of conjugated linoleic acid (CLA) (17,18). CLA is the collective name used for indicating two geometric and positional isomers of linoleic acid (C18:2), namely, cis 9 , trans 11 and trans 10 , cis 12 representing approximately 90% and 10% (respectively) of the total amount of CLA naturally found in ruminant foods (19).…”

Conjugated linoleic acid (CLA) influences muscle metabolism via stimulating mitochondrial biogenesis signaling in adult‐onset inactivity induced obese mice

“…Although the liver tissue analysis were not completed from the current study, it has been suggested that increased liver weight by CLA, particularly associated with the trans ‐10, cis ‐12 isomer, may be due to tremendous effects of CLA on fat mobilization from adipose tissue and increased hepatic lipogenesis . Others reported that the effect of CLA on hepatic steatosis was reversible and CLA also reduced high‐fat diet induced hepatic steatosis in rats . Recent meta analysis focusing on CLA and human liver function (as serum markers) reported that CLA supplementation is linked to an increase of one serum marker, aspartate aminotransferase (AST), whereas no links have been found with two other markers, alanine aminotrasnferase (ALT) and alkaline phosphatase (ALP) .…”