Palmitoleic acid reduces high fat diet-induced liver inflammation by promoting PPAR-γ-independent M2a polarization of myeloid cells

Abstract

Palmitoleic acid (POA, 16:1n-7) is a lipokine that has potential nutraceutical use to treat non-alcoholic fatty liver disease. We tested the effects of POA supplementation (daily oral gavage, 300 mg/Kg, 15 days) on murine liver inflammation induced by a high fat diet (HFD, 59% fat, 12 weeks). In HFD-fed mice, POA supplementation reduced serum insulin and improved insulin tolerance compared with oleic acid (OA, 300 mg/Kg). The livers of POA-treated mice exhibited less steatosis and inflammation than those of OA-treated mice with lower inflammatory cytokine levels and reduced toll-like receptor 4 protein content. The anti-inflammatory effects of POA in the liver were accompanied by a reduction in liver macrophages (LM, CD11c + ; F4/80 + ; CD86 + ), an effect that could be triggered by peroxisome proliferator activated receptor (PPAR)-γ, a lipogenic transcription factor upregulated in livers of POA-treated mice. We also used HFD-fed mice with selective deletion of PPAR-γ in myeloid cells (PPAR-γ KO LyzCre+ ) to test whether the beneficial anti-inflammatory effects of POA are dependent on macrophages PPAR-γ. POA-mediated improvement of insulin tolerance was tightly dependent on myeloid PPAR-γ, while POA anti-inflammatory actions including the reduction in liver inflammatory cytokines were preserved in mice bearing myeloid cells deficient in PPAR-γ. This overlapped with increased CD206 + (M2a) cells and downregulation of CD86 + and CD11c + liver macrophages. Moreover, POA supplementation increased hepatic AMPK activity and decreased expression of the fatty acid binding scavenger receptor, CD36. We conclude that POA controls liver inflammation triggered by fat accumulation through induction of M2a macrophages independently of myeloid cell PPAR-γ.

Activation of the Peroxisome Proliferator-Activated Receptors (PPAR-α/γ) and the Fatty Acid Metabolizing Enzyme Protein CPT1A by Camel Milk Treatment Counteracts the High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease

“…The present results are in accordance with recent studies that reported decreased IR, hepatic steatosis, and inflammatory reactions in animals receiving HFD after the restoration of the normal PPAR- γ expression by swimming exercises and palmitoleic acid supplementation [ 42 , 43 ].…”

Tetrahydroxanthohumol, a xanthohumol derivative, attenuates high-fat diet-induced hepatic steatosis by antagonizing PPARγ

“…The role for Plin4 in hepatic steatosis is limited, but it may affect TAG accumulation during HFD feeding ( Griffin, 2017 ). Ablation of Pparg in murine myeloid cells increased insulin resistance ( Souza et al, 2020 ) and ablation in macrophages and hepatic stellate cells, but not hepatocytes increased inflammation ( Morán-Salvador et al, 2013 ). Nevertheless, we did not observe either of these conditions in our study.…”

The Immunometabolic Roles of Various Fatty Acids in Macrophages and Lymphocytes

“…However, their relationships with palmitoleic acid are unclear, since this FA exhibits an anti-inflammatory effect in vitro [50,51], which seems to involve AMPK activation [50]. On the other hand, palmitoleic acid promotes the differentiation of macrophages into the M2 phenotype independent of the lipid sensor PPARγ [52]. In this sense, the balance between FA oxidation and FA synthesis may be essential to macrophage polarization and function.…”

“…This may be why palmitic acid co-stimulates the LPS/TLR-4 system. The anti-inflammatory effects of palmitoleic acid may be due to a reduction in CD36 expression and subsequent decline in FA uptake [52]. Molecular docking experiments showed that palmitoleic acid has a high affinity with the F126 loop site of MD2, a TLR-4 adaptor essential for canonical activation of the TLR-4 pathway.…”