LPIN1 is a new target gene for essential hypertension.
Journal
Journal of hypertension
ISSN: 1473-5598
Titre abrégé: J Hypertens
Pays: Netherlands
ID NLM: 8306882
Informations de publication
Date de publication:
01 03 2022
01 03 2022
Historique:
pubmed:
14
11
2021
medline:
24
3
2022
entrez:
13
11
2021
Statut:
ppublish
Résumé
We previously showed Lipin1 (LPIN1) to be a candidate gene for essential hypertension by genome-wide association studies. LPIN1 encodes the Lipin 1 protein, which contributes to the maintenance of lipid metabolism and glucose homeostasis. However, little is known about the association between LPIN1 and blood pressure (BP). We evaluated the BP of LPIN1-deficient [fatty liver dystrophy (fld)] mice and explored related mechanisms. Fld mice have very low expression of LPIN1 and exhibit fatty liver, hypertriglyceridemia, insulin resistance and peripheral neuropathy. Fld mice had significantly elevated SBP and heart rate (HR) throughout the day as measured by a radiotelemetric method. Diurnal variation of SBP and HR was also absent in fld mice. Furthermore, urinary excretion of adrenaline and noradrenaline by fld mice was significantly higher compared with that of control mice. The BP response of fld mice to clonidine (a centrally acting α2-adrenergic receptor agonist) was greater than that of control mice. However, levels of Angiotensinogen and Renin 1 mRNA and urinary nitric oxide excretion were comparable between the two groups. The decrease in SBP at 8 weeks after fat grafting surgery was significantly greater in the transplant group compared with the sham operated group. The elevated BP in fld mice may result from activation of the sympathetic nervous system through decreased levels of adipose cytokines. These results indicate that LPIN1 plays a crucial role in blood pressure regulation and that LPIN1 is a new target gene for essential hypertension.
Sections du résumé
BACKGROUND
We previously showed Lipin1 (LPIN1) to be a candidate gene for essential hypertension by genome-wide association studies. LPIN1 encodes the Lipin 1 protein, which contributes to the maintenance of lipid metabolism and glucose homeostasis. However, little is known about the association between LPIN1 and blood pressure (BP).
METHODS
We evaluated the BP of LPIN1-deficient [fatty liver dystrophy (fld)] mice and explored related mechanisms.
RESULTS
Fld mice have very low expression of LPIN1 and exhibit fatty liver, hypertriglyceridemia, insulin resistance and peripheral neuropathy. Fld mice had significantly elevated SBP and heart rate (HR) throughout the day as measured by a radiotelemetric method. Diurnal variation of SBP and HR was also absent in fld mice. Furthermore, urinary excretion of adrenaline and noradrenaline by fld mice was significantly higher compared with that of control mice. The BP response of fld mice to clonidine (a centrally acting α2-adrenergic receptor agonist) was greater than that of control mice. However, levels of Angiotensinogen and Renin 1 mRNA and urinary nitric oxide excretion were comparable between the two groups. The decrease in SBP at 8 weeks after fat grafting surgery was significantly greater in the transplant group compared with the sham operated group.
CONCLUSION
The elevated BP in fld mice may result from activation of the sympathetic nervous system through decreased levels of adipose cytokines. These results indicate that LPIN1 plays a crucial role in blood pressure regulation and that LPIN1 is a new target gene for essential hypertension.
Identifiants
pubmed: 34772856
doi: 10.1097/HJH.0000000000003046
pii: 00004872-202203000-00015
doi:
Substances chimiques
Lpin1 protein, mouse
EC 3.1.3.4
Phosphatidate Phosphatase
EC 3.1.3.4
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
536-543Informations de copyright
Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.
Références
Yatsu K, Mizuki N, Hirawa N, Oka A, Itoh N, Yamane T, et al. High-resolution mapping for essential hypertension using microsatellite markers. Hypertension 2007; 49:446–452.
Zhu X, Luke A, Cooper RS, Quertermous T, Hanis C, Mosley T, et al. Admixture mapping for hypertension loci with genome-scan markers. Nat Genet 2005; 37:177–181.
Ong KL, Leung RY, Wong LY, Cherny SS, Sham PC, Lam TH, et al. Association of a polymorphism in the lipin 1 gene with systolic blood pressure in men. Am J Hypertens 2008; 21:539–545.
Wiedmann S, Fischer M, Koehler M, Neureuther K, Riegger G, Doering A, et al. Genetic variants within the LPIN1 gene, encoding lipin, are influencing phenotypes of the metabolic syndrome in humans. Diabetes 2008; 57:209–217.
Reue K, Zhang P. The lipin protein family: dual roles in lipid biosynthesis and gene expression. FEBS Lett 2008; 582:90–96.
Chang YC, Chang LY, Chang TJ, Jiang YD, Lee KC, Kuo SS, et al. The associations of LPIN1 gene expression in adipose tissue with metabolic phenotypes in the Chinese population. Obesity (Silver Spring) 2010; 18:7–12.
Péterfy M, Phan J, Xu P, Reue K. Lipodystrophy in the fld mouse results from mutation of a new gene encoding a nuclear protein, lipin. Nat Genet 2001; 27:121–124.
Chen Y, Rui BB, Tang LY, Hu CM. Lipin family proteins--key regulators in lipid metabolism. Ann Nutr Metab 2015; 66:10–18.
Reue K, Xu P, Wang XP, Slavin BG. Adipose tissue deficiency, glucose intolerance, and increased atherosclerosis result from mutation in the mouse fatty liver dystrophy (fld) gene. J Lipid Res 2000; 41:1067–1076.
Gazit V, Weymann A, Hartman E, Finck BN, Hruz PW, Tzekov A, et al. Liver regeneration is impaired in lipodystrophic fatty liver dystrophy mice. Hepatology 2010; 52:2109–2117.
Langner CA, Birkenmeier EH, Ben-Zeev O, Schotz MC, Sweet HO, Davisson MT, et al. The fatty liver dystrophy (fld) mutation. A new mutant mouse with a developmental abnormality in triglyceride metabolism and associated tissue-specific defects in lipoprotein lipase and hepatic lipase activities. J Biol Chem 1989; 264:7994–8003.
Bergounioux J, Brassier A, Rambaud C, Bustarret O, Michot C, Hubert L, et al. Fatal rhabdomyolysis in 2 children with LPIN1 mutations. J Pediatr 2012; 160:1052–1054.
Zeharia A, Shaag A, Houtkooper RH, Hindi T, de Lonlay P, Erez G, et al. Mutations in LPIN1 cause recurrent acute myoglobinuria in childhood. Am J Hum Genet 2008; 83:489–494.
Kok BP, Kienesberger PC, Dyck JR, Brindley DN. Relationship of glucose and oleate metabolism to cardiac function in lipin-1 deficient (fld) mice. J Lipid Res 2012; 53:105–118.
Chen Z, Gropler MC, Norris J, Lawrence JC Jr, Harris TE, Finck BN. Alterations in hepatic metabolism in fld mice reveal a role for lipin 1 in regulating VLDL-triacylglyceride secretion. Arterioscler Thromb Vasc Biol 2008; 28:1738–1744.
Kobayashi Y, Hirawa N, Tabara Y, Muraoka H, Fujita M, Miyazaki N, et al. Mice lacking hypertension candidate gene ATP2B1 in vascular smooth muscle cells show significant blood pressure elevation. Hypertension 2012; 59:854–860.
Yeo JH, Yoon SY, Kim SJ, Oh SB, Lee JH, Beitz AJ, et al. Clonidine, an alpha-2 adrenoceptor agonist relieves mechanical allodynia in oxaliplatin-induced neuropathic mice; potentiation by spinal p38 MAPK inhibition without motor dysfunction and hypotension. Int J Cancer 2016; 138:2466–2476.
Tsunoda M, Yamagishi M, Imai K, Yanagisawa T. Study of the acute cardiovascular effects of several antihypertensive agents with the measurement of plasma catecholamines in mice. Anal Bioanal Chem 2009; 394:947–952.
Maeda A, Tamura K, Wakui H, Dejima T, Ohsawa M, Azushima K, et al. Angiotensin receptor-binding protein ATRAP/Agtrap inhibits metabolic dysfunction with visceral obesity. J Am Heart Assoc 2013; 2:e000312.
Tran TT, Yamamoto Y, Gesta S, Kahn CR. Beneficial effects of subcutaneous fat transplantation on metabolism. Cell Metab 2008; 7:410–420.
Langner CA, Birkenmeier EH, Roth KA, Bronson RT, Gordon JI. Characterization of the peripheral neuropathy in neonatal and adult mice that are homozygous for the fatty liver dystrophy (fld) mutation. J Biol Chem 1991; 266:11955–11964.
Oishi K, Amagai N, Shirai H, Kadota K, Ohkura N, Ishida N. Genome-wide expression analysis reveals 100 adrenal gland-dependent circadian genes in the mouse liver. DNA Res 2005; 12:191–202.
Chowdhury D, Wang C, Lu A, Zhu H. Identifying transcription factor combinations to modulate circadian rhythms by leveraging virtual knockouts on transcription networks. iScience 2020; 23:101490.
Damase-Michel C, Valet P, Montastruc JL. Nicardipine causes sympathetic activation that does not involve baroreceptor reflex tachycardia in conscious sinoaortic-denervated dogs. Eur J Pharmacol 1987; 142:145–149.
Prados P, Santa T, Homma H, Doi H, Narita H, Del Castillo B, et al. Comparison of the sympathetic nervous system activity between spontaneously hypertensive and Wistar-Kyoto rats to respond to blood pressure reduction. Biol Pharm Bull 1997; 20:341–344.
Tanida M, Shen J, Horii Y, Matsuda M, Kihara S, Funahashi T, et al. Effects of adiponectin on the renal sympathetic nerve activity and blood pressure in rats. Exp Biol Med (Maywood) 2007; 232:390–397.
Hoyda TD, Smith PM, Ferguson AV. Adiponectin acts in the nucleus of the solitary tract to decrease blood pressure by modulating the excitability of neuropeptide Y neurons. Brain Res 2009; 1256:76–84.
Haynes WG, Sivitz WI, Morgan DA, Walsh SA, Mark AL. Sympathetic and cardiorenal actions of leptin. Hypertension 1997; 30:619–623.
Simonds SE, Pryor JT, Ravussin E, Greenway FL, Dileone R, Allen AM, et al. Leptin mediates the increase in blood pressure associated with obesity. Cell 2014; 159:1404–1416.
Mark AL, Shaffer RA, Correia ML, Morgan DA, Sigmund CD, Haynes WG. Contrasting blood pressure effects of obesity in leptin-deficient ob/ob mice and agouti yellow obese mice. J Hypertens 1999; 17:1949–1953.
Aizawa-Abe M, Ogawa Y, Masuzaki H, Ebihara K, Satoh N, Iwai H, et al. Pathophysiological role of leptin in obesity-related hypertension. J Clin Invest 2000; 105:1243–1252.
Bravo PE, Morse S, Borne DM, Aguilar EA, Reisin E. Leptin and hypertension in obesity. Vasc Health Risk Manag 2006; 2:163–169.
Landsberg L. Insulin and the sympathetic nervous system in the pathophysiology of hypertension. Blood Press Suppl 1996; 1:25–29.
Vollenweider P, Tappy L, Randin D, Schneiter P, Jequier E, Nicod P, et al. Differential effects of hyperinsulinemia and carbohydrate metabolism on sympathetic nerve activity and muscle blood flow in humans. J Clin Invest 1993; 92:147–154.
da Silva AA, do Carmo JM, Li X, Wang Z, Mouton AJ, Hall JE. Role of hyperinsulinemia and insulin resistance in hypertension: metabolic syndrome revisited. Can J Cardiol 2020; 36:671–682.
Lu H, Cassis LA, Kooi CW, Daugherty A. Structure and functions of angiotensinogen. Hypertens Res 2016; 39:492–500.
Bełtowski J. Role of leptin in blood pressure regulation and arterial hypertension. J Hypertens 2006; 24:789–801.
Gavrilova O, Marcus-Samuels B, Graham D, Kim JK, Shulman GI, Castle AL, et al. Surgical implantation of adipose tissue reverses diabetes in lipoatrophic mice. J Clin Invest 2000; 105:271–278.
Colombo C, Cutson JJ, Yamauchi T, Vinson C, Kadowaki T, Gavrilova O, et al. Transplantation of adipose tissue lacking leptin is unable to reverse the metabolic abnormalities associated with lipoatrophy. Diabetes 2002; 51:2727–2733.