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Cathelicidin suppresses lipid accumulation and hepatic steatosis by inhibition of the CD36 receptor.

ABSTRACT: Obesity is a global epidemic which increases the risk of the metabolic syndrome. Cathelicidin (LL-37 and mCRAMP) is an antimicrobial peptide with an unknown role in obesity. We hypothesize that cathelicidin expression correlates with obesity and modulates fat mass and hepatic steatosis.Male C57BL/6?J mice were fed a high-fat diet. Streptozotocin was injected into mice to induce diabetes. Experimental groups were injected with cathelicidin and CD36 overexpressing lentiviruses. Human mesenteric fat adipocytes, mouse 3T3-L1 differentiated adipocytes and human HepG2 hepatocytes were used in the in vitro experiments. Cathelicidin levels in non-diabetic, prediabetic and type II diabetic patients were measured by enzyme-linked immunosorbent assay.Lentiviral cathelicidin overexpression reduced hepatic steatosis and decreased the fat mass of high-fat diet-treated diabetic mice. Cathelicidin overexpression reduced mesenteric fat and hepatic fatty acid translocase (CD36) expression that was reversed by lentiviral CD36 overexpression. Exposure of adipocytes and hepatocytes to cathelicidin significantly inhibited CD36 expression and reduced lipid accumulation. Serum cathelicidin protein levels were significantly increased in non-diabetic and prediabetic patients with obesity, compared with non-diabetic patients with normal body mass index (BMI) values. Prediabetic patients had lower serum cathelicidin protein levels than non-diabetic subjects.Cathelicidin inhibits the CD36 fat receptor and lipid accumulation in adipocytes and hepatocytes, leading to a reduction of fat mass and hepatic steatosis in vivo. Circulating cathelicidin levels are associated with increased BMI. Our results demonstrate that cathelicidin modulates the development of obesity.

SUBMITTER: Hoang-Yen Tran D

PROVIDER: S-EPMC5014693 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Cathelicidin suppresses lipid accumulation and hepatic steatosis by inhibition of the CD36 receptor.

Hoang-Yen Tran D D Hoang-Ngoc Tran D D Mattai S A SA Sallam T T Ortiz C C Lee E C EC Robbins L L Ho S S Lee J E JE Fisseha E E Shieh C C Sideri A A Shih D Q DQ Fleshner P P McGovern D P B DP Vu M M Hing T C TC Bakirtzi K K Cheng M M Su B B Law I I Karagiannides I I Targan S R SR Gallo R L RL Li Z Z Koon H W HW

International journal of obesity (2005) 20160510 9

<h4>Background and objectives</h4>Obesity is a global epidemic which increases the risk of the metabolic syndrome. Cathelicidin (LL-37 and mCRAMP) is an antimicrobial peptide with an unknown role in obesity. We hypothesize that cathelicidin expression correlates with obesity and modulates fat mass and hepatic steatosis.<h4>Materials and methods</h4>Male C57BL/6 J mice were fed a high-fat diet. Streptozotocin was injected into mice to induce diabetes. Experimental groups were injected with cathel ...[more]

PMID: 27163748

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Project description:Background/aimsLiver lipid accumulation induced by high-fat diet (HFD) is an early onset process of non-alcoholic fatty liver diseases (NAFLD). Protein kinase A (PKA) is known to be involved in hepatic lipid metabolism. However, the role of PKA in NAFLD has not been well tested in vivo due to the lack of optimal PKA deficient mouse model.MethodsA novel PKA-specific inhibitor gene was conditionally overexpressed in mouse (PKAi mouse) liver using LoxP/Cre system. PKA activity in the liver extract was measured with a commercial assay kit. The PKAi and control mice of 8-week age, were subjected to HFD or chow diet (CD) for 2 months. Body weight, liver index, and triglyceride in the liver were measured. RNA sequencing was performed for the liver tissues and analyzed with Gene Ontology (GO) and pathway enrichment.ResultsPKAi-GFP protein was overexpressed in the liver and the PKA activation was significantly inhibited in the liver of PKAi mouse. When fed with CD, RNA sequencing revealed 56 up-regulated and 51 down-regulated genes in PKAi mice compared with control mice, which were mainly involved in lipid metabolism though no significant differences in the body weight, liver index, triglyceride accumulation were observed between PKAi and control mice. However, when fed with HFD for 2 months, the liver was enlarged more, and the accumulation of triglyceride in the liver was more severe in PKAi mice. When comparing the transcriptomes of CD-fed and HFD-fed control mice, GO enrichment showed that the genes down-regulated by HFD were mainly enriched in immune-related GO terms, and up-regulated genes were enriched in metabolism. When comparing the transcriptomes of CD-fed and HFD-fed PKAi mice, GO analysis showed that the down-regulated genes were enriched in metabolism, while the up-regulated genes were clustered in ER stress-related pathways. When comparing HFD-fed PKAi and HFD-fed control mice, the genes with lower expression level in PKAi mice were enriched in the lipoprotein synthesis, which might explain that more TG is accumulated in PKAi liver after HFD feeding.ConclusionsReduced PKA activity could be a factor promoting the TG accumulation in the liver and the development of NAFLD.

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Cathelicidin suppresses lipid accumulation and hepatic steatosis by inhibition of the CD36 receptor.

Publications

Cathelicidin suppresses lipid accumulation and hepatic steatosis by inhibition of the CD36 receptor.

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