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Palmitoleic acid reduces high fat diet-induced liver inflammation by promoting PPAR-?-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)-?, a lipogenic transcription factor upregulated in livers of POA-treated mice. We also used HFD-fed mice with selective deletion of PPAR-? in myeloid cells (PPAR-? KOLyzCre+) to test whether the beneficial anti-inflammatory effects of POA are dependent on macrophages PPAR-?. POA-mediated improvement of insulin tolerance was tightly dependent on myeloid PPAR-?, while POA anti-inflammatory actions including the reduction in liver inflammatory cytokines were preserved in mice bearing myeloid cells deficient in PPAR-?. 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-?.

SUBMITTER: Souza CO

PROVIDER: S-EPMC7487782 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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

Souza Camila O CO Teixeira Alexandre A S AAS Biondo Luana Amorim LA Silveira Loreana Sanches LS de Souza Breda Cristiane N CN Braga Tarcio T TT Camara Niels O S NOS Belchior Thiago T Festuccia William T WT Diniz Tiego A TA Ferreira Glaucio Monteiro GM Hirata Mario Hiroyuki MH Chaves-Filho Adriano B AB Yoshinaga Marcos Y MY Miyamoto Sayuri S Calder Philip C PC Sethi Jaswinder K JK Rosa Neto José C JC

Biochimica et biophysica acta. Molecular and cell biology of lipids 20200730 10

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 t ...[more]

PMID: 32738301

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Project description:Pioglitazone (Pio) is a thiazolidinedione (TZD) insulin-sensitizing drug whose effects result predominantly from its modulation of the transcriptional activity of peroxisome proliferator-activated-receptor-gamma (PPARγ). Pio is used to treat human insulin-resistant diabetes and also frequently considered for treatment of nonalcoholic steatohepatitis (NASH). In both settings, Pio's beneficial effects are believed to result primarily from its actions on adipose PPARγ activity, which improves insulin sensitivity and reduces the delivery of fatty acids to the liver. Nevertheless, a recent clinical trial showed variable efficacy of Pio in human NASH. Hepatocytes also express PPARγ, and such expression increases with insulin resistance and in nonalcoholic fatty liver disease (NAFLD). Furthermore, mice that overexpress hepatocellular PPARγ and Pio-treated mice with extrahepatic PPARγ gene disruption develop features of NAFLD. Thus, Pio's direct impact on hepatocellular gene expression might also be a determinant of this drug's ultimate influence on insulin resistance and NAFLD. Previous studies have characterized Pio's PPARγ-dependent effects on hepatic expression of specific adipogenic, lipogenic, and other metabolic genes. However, such transcriptional regulation has not been comprehensively assessed. The studies reported here address that consideration by genome-wide comparisons of Pio's hepatic transcriptional effects in wildtype (WT) and liver-specific PPARγ-knockout (KO) mice given either control or high-fat (HFD) diets. The results identify a large set of hepatic genes for which Pio's liver PPARγ-dependent transcriptional effects are concordant with its effects on RXR-DNA binding in WT mice. These data also show that HFD modifies Pio's influence on a subset of such transcriptional regulation. Finally, our findings reveal a broader influence of Pio on PPARγ-dependent hepatic expression of nuclear genes encoding mitochondrial proteins than previously recognized. Taken together, these studies provide new insights about the tissue-specific mechanisms by which Pio affects hepatic gene expression and the broad scope of this drug's influence on such regulation.

Dataset Information

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

Publications

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

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