Establishment of a Transgenic Mouse Model Specifically Expressing Human Serum Amyloid A in Adipose Tissue

Olsson, Maja; Ahlin, Sofie; Olsson, Bob; Svensson, Per‐Arne; Ståhlman, Marcus; Borén, Jan; Carlsson, Lena; Sjöholm, Kajsa

doi:10.1371/journal.pone.0019609

Cited by 12 publications

(20 citation statements)

References 49 publications

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“…As expected, the major site of expression of both transgenes was in adipose tissue. Expression levels of PNPLA3 were 3-fold higher in brown fat than in white fat ( Figure 1B), which is similar to the expression pattern seen with this promoter in other transgenic lines (32,33). Similar levels of PNPLA3 were present in the lipid droplets in the adipose tissues of the 2 transgenic mouse lines ( Figure 1B).…”

Section: Introductionsupporting

confidence: 79%

Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis

et al. 2012

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A genetic variant in PNPLA3 (PNPLA3 I148M ), a triacylglycerol (TAG) hydrolase, is a major risk factor for nonalcoholic fatty liver disease (NAFLD); however, the mechanism underlying this association is not known. To develop an animal model of PNPLA3-induced fatty liver disease, we generated transgenic mice that overexpress similar amounts of wild-type PNPLA3 (PNPLA3 WT ) or mutant PNPLA3 (PNPLA3 I148M ) either in liver or adipose tissue. Overexpression of the transgenes in adipose tissue did not affect liver fat content. Expression of PNPLA3 I148M , but not PNPLA3 WT , in liver recapitulated the fatty liver phenotype as well as other metabolic features associated with this allele in humans. Metabolic studies provided evidence for 3 distinct alterations in hepatic TAG metabolism in PNPLA3 I148M transgenic mice: increased formation of fatty acids and TAG, impaired hydrolysis of TAG, and relative depletion of TAG long-chain polyunsaturated fatty acids. These findings suggest that PNPLA3 plays a role in remodeling TAG in lipid droplets, as they accumulate in response to food intake, and that the increase in hepatic TAG levels associated with the I148M substitution results from multiple changes in hepatic TAG metabolism. The development of an animal model that recapitulates the metabolic phenotype of the allele in humans provides a new platform in which to elucidate the role of PNLPA3 I148M in NAFLD.

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Section: Introductionsupporting

confidence: 79%

Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis

et al. 2012

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“…The crystal structure of SAA1.1 has shown for the first time the α-helix bundle of this acute-phase protein, and provides insights into the mechanism by which heparin facilitates the conversion of SAA1 to AA (Lu et al, 2014). Genetically altered mice carrying the SAA1 transgenes (Olsson et al, 2011; Ji et al, 2015) or deletion of the Saa1 and Saa2 loci (de Beer et al, 2010) have allowed examination of the SAA protein of interest for its functions in whole animals. The use of these new approaches is expected to greatly facilitate research on SAA1 and other SAA proteins.…”

Section: Discussionmentioning

confidence: 99%

“…Transgenic mice expressing human SAA1 in adipocytes have been prepared (Olsson et al, 2011). Using these mice, the involvement of SAA1 in the development of insulin resistance or obesity-related inflammation was examined.…”

Section: Saa In Other Speciesmentioning

confidence: 99%

Serum amyloid A1: Structure, function and gene polymorphism

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2016

Gene

164

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Inducible expression of serum amyloid A (SAA) is a hallmark of the acute-phase response, which is a conserved reaction of vertebrates to environmental challenges such as tissue injury, infection and surgery. Human SAA1 is encoded by one of the four SAA genes and is the best-characterized SAA protein. Initially known as a major precursor of amyloid A (AA), SAA1 has been found to play an important role in lipid metabolism and contributes to bacterial clearance, the regulation of inflammation and tumor pathogenesis. SAA1 has five polymorphic coding alleles (SAA1.1 – SAA1.5) that encode distinct proteins with minor amino acid substitutions. Single nucleotide polymorphism (SNP) has been identified in both the coding and non-coding regions of human SAA1. Despite high levels of sequence homology among these variants, SAA1 polymorphisms have been reported as risk factors of cardiovascular diseases and several types of cancer. A recently solved crystal structure of SAA1.1 reveals a hexameric bundle with each of the SAA1 subunits assuming a 4-helix structure stabilized by the C-terminal tail. Analysis of the native SAA1.1 structure has led to the identification of a competing site for high-density lipoprotein (HDL) and heparin, thus providing the structural basis for a role of heparin and heparan sulfate in the conversion of SAA1 to AA. In this brief review, we compares human SAA1 with other forms of human and mouse SAAs, and discuss how structural and genetic studies of SAA1 have advanced our understanding of the physiological functions of the SAA proteins.

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“…The generation of hSAA1 +/− transgenic mice (hSAA1 mice) expressing human SAA1 in the adipose tissue under the control of the aP2 promoter has previously been reported [32]. The hSAA1 mice display moderately elevated circulating levels of SAA where SAA is found in the HDL-containing lipoprotein fraction.…”

Section: Methodsmentioning

confidence: 99%

“…We have previously reported the generation of a transgenic mouse model expressing human SAA1 (hSAA1) in the adipose tissue with moderately elevated circulating levels of SAA comparable those seen in human obesity [32]. In this study we used this model to investigate whether adipose tissue-derived hSAA1 plays a direct role in obesity-related inflammation and the development of insulin resistance.…”

Section: Introductionmentioning

confidence: 99%

No Evidence for a Role of Adipose Tissue-Derived Serum Amyloid A in the Development of Insulin Resistance or Obesity-Related Inflammation in hSAA1+/− Transgenic Mice

Ahlin

Olsson

et al. 2013

PLoS ONE

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Obesity is associated with a low-grade inflammation including moderately increased serum levels of the acute phase protein serum amyloid A (SAA). In obesity, SAA is mainly produced from adipose tissue and serum levels of SAA are associated with insulin resistance. SAA has been described as a chemoattractant for inflammatory cells and adipose tissue from obese individuals contains increased numbers of macrophages. However, whether adipose tissue-derived SAA can have a direct impact on macrophage infiltration in adipose tissue or the development of insulin resistance is unknown. The aim of this study was to investigate the effects of adipose tissue-derived SAA1 on the development of insulin resistance and obesity-related inflammation. We have previously established a transgenic mouse model expressing human SAA1 in the adipose tissue. For this report, hSAA1+/− transgenic mice and wild type mice were fed with a high fat diet or normal chow. Effects of hSAA1 on glucose metabolism were assessed using an oral glucose tolerance test. Real-time PCR was used to measure the mRNA levels of macrophage markers and genes related to insulin sensitivity in adipose tissue. Cytokines during inflammation were analyzed using a Proinflammatory 7-plex Assay. We found similar insulin and glucose levels in hSAA1 mice and wt controls during an oral glucose tolerance test and no decrease in mRNA levels of genes related to insulin sensitivity in adipose tissue in neither male nor female hSAA1 animals. Furthermore, serum levels of proinflammatory cytokines and mRNA levels of macrophage markers in adipose tissue were not increased in hSAA1 mice. Hence, in this model we find no evidence that adipose tissue-derived hSAA1 influences the development of insulin resistance or obesity-related inflammation.

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Establishment of a Transgenic Mouse Model Specifically Expressing Human Serum Amyloid A in Adipose Tissue

Cited by 12 publications

References 49 publications

Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis

Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis

Serum amyloid A1: Structure, function and gene polymorphism

No Evidence for a Role of Adipose Tissue-Derived Serum Amyloid A in the Development of Insulin Resistance or Obesity-Related Inflammation in hSAA1+/− Transgenic Mice

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