PAHSAs enhance hepatic and systemic insulin sensitivity through direct and indirect mechanisms

Zhou, Peng; Santoro, Anna; Peroni, Odile D.; Nelson, Andrew T.; Saghatelian, Alan; Siegel, Dionicio; Kahn, Barbara B.

doi:10.1172/jci127092

Cited by 70 publications

(88 citation statements)

References 56 publications

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“…Pharmacological administration of 9-and/or 5-PAHSA improves glucose tolerance and insulin sensitivity in mice fed chow or HFD (1,4,5). This observation prompted us to test whether the increases we detected in endogenous 9-FAHFA levels in adipose tissue of Adtrp-KO and DKO mice are sufficient to influence glucose metabolism.…”

Section: Aig1 and Adtrp Deficiency Are Not Sufficient To Improve Glucmentioning

confidence: 89%

“…Oral administration of synthetic 5-and 9-PAHSA improved glucose tolerance in chow and HFD-fed mice. The effect in chow-fed mice was ascribed to the ability of these FAHFAs to induce glucagonlike peptide 1 (GLP-1) release and to directly stimulate insulin secretion (1,4) while in HFD-fed mice, the effect resulted from increased insulin sensitivity (5). PAHSA treatment also decreased expression of inflammatory cytokines in adipose tissue macrophages that accompanies obesity (1).…”

Section: Introductionmentioning

confidence: 99%

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AIG1 and ADTRP are endogenous hydrolases of fatty acid esters of hydroxy fatty acids (FAHFAs) in mice

Ertunc

Kok

Parsons

et al. 2020

Journal of Biological Chemistry

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Keywords: fatty acid ester of hydroxy fatty acid (FAHFA), threonine hydrolase, metabolism, androgeninduced gene 1(AIG1), androgen-dependent TFPI-regulating protein (ADTRP), lipid ester, enzyme inhibitor, diabetes, lipid signaling, glucose metabolism. AbstractFatty acid esters of hydroxy fatty acids (FAHFAs) are a newly discovered class of signaling lipids with anti-inflammatory and antidiabetic properties. However, the endogenous regulation of FAHFAs remains a pressing but unanswered question. Here, using MS-based FAHFA hydrolysis assays, LC-MS-based lipidomics analyses, and activity-based protein profiling, we found that androgen-induced gene 1 (AIG1) and androgen-dependent TFPI-regulating protein (ADTRP), two threonine hydrolases, control FAHFA levels in vivo in both genetic and pharmacologic mouse models. Tissues from mice lacking ADTRP (Adtrp-KO), or both AIG1 and ADTRP (DKO) had higher concentrations of FAHFAs particularly isomers with the ester bond at the 9 th carbon due to decreased FAHFA hydrolysis activity. The levels of other lipids were unaltered indicating that AIG1 and ADTRP specifically hydrolyze FAHFAs. Complementing these genetic studies, we also identified a dual AIG1/ADTRP inhibitor, ABD-110207, that is active in vivo. Acute treatment of wild-type mice with ABD-110207 resulted in elevated FAHFA levels, further supporting the notion that AIG1 and ADTRP activity control endogenous FAHFA levels. However, loss of AIG1/ADTRP did not mimic the changes associated with pharmacologically administered FAHFAs on circulating and tissue FAHFA levels, glucose tolerance or insulin sensitivity in mice, indicating that therapeutic strategies should continue to focus on FAHFA administration. Together, these findings identify AIG1 and ADTRP as the first endogenous FAHFA hydrolases identified and provide critical genetic and chemical tools for further characterization of these enzymes and endogenous FAHFAs to unravel their physiological functions and roles in health and disease.https://www.jbc.org/cgi/

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Section: Aig1 and Adtrp Deficiency Are Not Sufficient To Improve Glucmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

AIG1 and ADTRP are endogenous hydrolases of fatty acid esters of hydroxy fatty acids (FAHFAs) in mice

Ertunc

Kok

Parsons

et al. 2020

Journal of Biological Chemistry

Self Cite

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“…Endogenous 9-PAHSA has been shown to have a role in insulin sensitivity and as an anti-inflammatory and antioxidant agent [8,11]. In this study, we were interested in elucidating the preventive effects of 9-PAHSA ( Figure 1A) on steatosis in vitro.…”

Section: Pretreatment With 9-pahsa Prevented Mitochondrial Dysfunctiomentioning

confidence: 99%

“…Palmitic-acid-9-hydroxy-stearic-acid (9-PAHSA) is an isomeric form of a bioactive FAHFA [8]. In serum from insulin-resistant patients and insulin-sensitive mice, the endogenous 9-PAHSA level was found to be decreased [8] and increased [11], respectively. Additionally, 9-PAHSA exhibited anti-inflammatory properties [8].…”

Section: Introductionmentioning

confidence: 99%

9-PAHSA Prevents Mitochondrial Dysfunction and Increases the Viability of Steatotic Hepatocytes

Moreira

Rüschenbaum

Schefczyk

et al. 2020

IJMS

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Nonalcoholic fatty liver disease (NAFLD) is quickly becoming the most common liver disease worldwide. Within the NAFLD spectrum, patients with nonalcoholic steatohepatitis (NASH) are at the highest risk of developing cirrhosis and disease progression to hepatocellular carcinoma. To date, therapeutic options for NASH patients have been ineffective, and therefore, new options are urgently needed. Hence, a model system to develop new therapeutic interventions is needed. Here, we introduce two new in vitro models of steatosis induction in HepG2 cells and primary murine hepatocytes. We used a recently discovered novel class of bioactive anti-inflammatory lipids called branched fatty acid esters of hydroxyl fatty acids. Among these bioactive lipids, palmitic-acid-9-hydroxy-stearic-acid (9-PAHSA) is the most promising as a representative nondrug therapy based on dietary supplements or nutritional modifications. In this study, we show a therapeutic effect of 9-PAHSA on lipotoxicity in steatotic primary hepatocytes and HepG2 cells. This could be shown be increased viability and decreased steatosis. Furthermore, we could demonstrate a preventive effect in HepG2 cells. The outcome of 9-PAHSA administration is both preventative and therapeutically effective for hepatocytes with limited damage. In conclusion, bioactive lipids like 9-PAHSA offer new hope for prevention or treatment in patients with fatty liver and steatosis.

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“…In a recent follow-up study, the authors utilized euglycemichyperinsulinemic clamps for detailed metabolic characterization, and confirmed PAHSAs' role as insulin sensitizers [5]. To this end, the authors performed chronic dosing studies wherein PAHSA were delivered to aged chow-and HFD-fed mice via osmotic mini-pumps.…”

mentioning

confidence: 92%

Systemic and Organ-Specific Insulin Sensitizing Mechanisms of PAHSAs-Comments on Zhou and Santoro et al. PAHSAs Enhance Hepatic and Systemic Insulin Sensitivity through Direct and Indirect Mechanisms, J Clin Invest. 2019;129(10):4138–4150

Kumari¹,

Heeren²,

Scheja³

2020

Immunometabolism

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PAHSAs enhance hepatic and systemic insulin sensitivity through direct and indirect mechanisms

Cited by 70 publications

References 56 publications

AIG1 and ADTRP are endogenous hydrolases of fatty acid esters of hydroxy fatty acids (FAHFAs) in mice

AIG1 and ADTRP are endogenous hydrolases of fatty acid esters of hydroxy fatty acids (FAHFAs) in mice

9-PAHSA Prevents Mitochondrial Dysfunction and Increases the Viability of Steatotic Hepatocytes

Systemic and Organ-Specific Insulin Sensitizing Mechanisms of PAHSAs-Comments on Zhou and Santoro et al. PAHSAs Enhance Hepatic and Systemic Insulin Sensitivity through Direct and Indirect Mechanisms, J Clin Invest. 2019;129(10):4138–4150

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