Liver X receptors and its role in macrophage metabolism and function: a new approach to treat metabolic diseases

Author(s)

Jéssica Aparecida da Silva Pereira

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
• Defense date: 2022-02-01

Examining board members

Pedro Manoel Mendes de Moraes Vieira; José Donato Júnior; Luiz Osório Silveira Leiria; Patricia Torres Bozza Viola

• Advisor: Pedro Manoel Mendes de Moraes Vieira

Abstract

Liver X receptors (LXRs) are nuclear receptors activated by molecules derived from cholesterol metabolism. Cholesterol levels are commonly increased in obesity and contribute for the activation of pro-inflammatory responses. Obesity is characterized by increased lipid accumulation in white adipocytes and systemic chronic low-grade inflammation. LXRs are involved in the maintenance of cholesterol homeostasis, and also have a role in the regulation of immune response. The role of LXRs in obesity and how these receptors contribute to adipose tissue macrophage (ATM) phenotype and metabolic programming remains to be elucidated. Here, we show that LXR deletion impairs body weight gain and fat accumulation in mice. LXR &#223KO mice has increased insulin sensitivity and a preferential usage of carbohydrates as fuel to energy production. LXR &#945-depleted but not LXR &#223-depleted animals display increased insulin sensitivity with no changes in the energy fuel usage preference compared to WT mice. ATMs from obese animals have enriched cholesterol pathway, and LXR deletion boost the lipid accumulation in macrophages, while increase the adipose tissue inflammation by inducing IL-1 &#223 and TNF- &#945 in ATMs in a LXR &#223-dependent manner. In the absence of metabolic stress, the lack of any LXR isoform leads to adipose tissue inflammation with increased CD11c &#43 ATMs. Also the LXR deletion specifically in immune cells contribute for the disruption of adipose tissue immune balance, marked by the increase in CD11c+ and IL-1 &#223 &#43 ATMs as enhanced monocyte infiltration on AT. Moreover, the deletion of LXR in immune cells aggravates obesity-induced adipose tissue inflammation without promote changes in glucose homeostasis. We found that naringenin (NAR) is an LXR agonist in macrophages. NAR induces LXR-target genes expression and reduces the secretion of proinflammatory cytokines in LPS-activated and LPS &#43IFN &#947-activated macrophages by reducing glycolysis and mitochondrial dysfunction. In addition, obese mice treated with NAR display increased insulin sensitivity and reduced AT inflammation, as observed by the reduction on CD11c &#43, IL-1 &#223+ and TNF- &#945 &#43 ATMs and reduced monocyte infiltration compared to obese control group. Together our results show that each LXR isoform displays a distinct role in the regulation of systemic glucose homeostasis and adipose tissue inflammation. LXR &#223 expression in immune cells is essential for the pro/anti-inflammatory balance of the adipose tissue. LXR &#223 has the potential to become a novel therapeutic target to treat adipose tissue inflammation and insulin resistance. (AU)

• FAPESP's process: 17/00079-7 - Effects of LXRs receptor activation on systemic metabolic parameters and on the metabolic modulation of resident tissue macrophages of adipose tissue
• Grantee: Jéssica Aparecida da Silva Pereira
• Support Opportunities: Scholarships in Brazil - Doctorate