Hepatic Steatosis and Ectopic Fat Are Associated With Differences in Subcutaneous Adipose Tissue Gene Expression in People With HIV

Curtis L Gabriel, Fei Ye, Run Fan, Sangeeta Nair, James G Terry, John Jeffrey Carr, Heidi Silver, Paxton Baker, LaToya Hannah, Celestine Wanjalla, Mona Mashayekhi, Sam Bailin, Morgan Lima, Beverly Woodward, Manhal Izzy, Jane F Ferguson, John R Koethe, Curtis L Gabriel, Fei Ye, Run Fan, Sangeeta Nair, James G Terry, John Jeffrey Carr, Heidi Silver, Paxton Baker, LaToya Hannah, Celestine Wanjalla, Mona Mashayekhi, Sam Bailin, Morgan Lima, Beverly Woodward, Manhal Izzy, Jane F Ferguson, John R Koethe

Abstract

Persons with human immunodeficiency virus (PWH) have subcutaneous adipose tissue (SAT) dysfunction related to antiretroviral therapy and direct viral effects, which may contribute to a higher risk of nonalcoholic fatty liver disease compared with human immunodeficiency virus-negative individuals. We assessed relationships between SAT expression of major adipocyte regulatory and lipid storage genes with hepatic and other ectopic lipid deposits in PWH. We enrolled 97 PWH on long-term antiretroviral therapy with suppressed plasma viremia and performed computed tomography measurements of liver attenuation, a measure of hepatic steatosis, skeletal muscle (SM) attenuation, and the volume of abdominal subcutaneous, visceral, and pericardial adipose tissue. Whole SAT gene expression was measured using the Nanostring platform, and relationships with computed tomography imaging and fasting lipids were assessed using multivariable linear regression and network mapping. The cohort had a mean age of 47 years, body mass index of 33.4 kg/m2, and CD4 count of 492 cells/mm3. Lower liver attenuation, a marker of greater steatosis, was associated with differences in SAT gene expression, including lower lipoprotein lipase and acyl-CoA dehydrogenase, and higher phospholipid transfer protein. Lower liver attenuation clustered with lower visceral adipose tissue (VAT) attenuation and greater VAT volume, pericardial fat volume and triglycerides, but no relationship was observed between liver attenuation and SAT volume, SM attenuation, or low-density lipoprotein. Conclusion: Liver attenuation was associated with altered SAT expression of genes regulating lipid metabolism and storage, suggesting that SAT dysfunction may contribute to nonalcoholic fatty liver disease in PWH. SAT gene-expression relationships were similar for VAT volume and attenuation, but not SM, indicating that ectopic lipid deposition may involve multiple pathways.

© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of the American Association for the Study of Liver Diseases.

Figures

FIG. 1
FIG. 1
Relationships among BMI, fasting lipids, and adipose tissue depot size and density. Spearman correlation coefficients between tissue density (HU), tissue volume, fasting plasma lipids, and BMI in 97 PWH. •P < 0.05, ••P < 0.01. Abbreviation: TG, triglyceride.
FIG. 2
FIG. 2
Correlation of SAT gene expression with fasting lipids, adipose tissue depot size, or tissue density. Heatmap showing relationships between whole adipose tissue gene expression (columns) with fasting lipids and CT characteristics of tissue depots (rows) using adjusted Spearman correlations. Models were adjusted for age, sex, race, BMI, diabetes status, CD4 count at clinic enrollment, duration of ART, exposure to AZT or d4T antiviral therapy, and batch effect (see Supplementary Material).
FIG. 3
FIG. 3
Network analysis of gene–tissue relationships. All relationships between gene expression and tissue depots with raw P value < 0.05 are shown. Larger node size represents a greater degree of connectivity with other nodes. Connecting lines are darker and wider for smaller raw P values between expression of individual genes and plasma lipid levels or tissue characteristics on CT variables and gene expression (see Supplementary Material).

References

    1. Weber R, Sabin CA, Friis‐Møller N, Reiss P, El‐Sadr WM, Kirk O, et al. Liver‐related deaths in persons infected with the human immunodeficiency virus: the D:A: D study. Arch Intern Med 2006;166:1632‐1641.
    1. Nansseu JR, Bigna JJ, Kaze AD, Noubiap JJ. Incidence and risk factors for prediabetes and diabetes mellitus among HIV‐infected adults on antiretroviral therapy: a systematic review and meta‐analysis. Epidemiology 2018;29:431‐441.
    1. Currier JS, Lundgren JD, Carr A, Klein D, Sabin CA, Sax PE, et al. Epidemiological evidence for cardiovascular disease in HIV‐infected patients and relationship to highly active antiretroviral therapy. Circulation 2008;118:e29‐e35.
    1. Maurice JB, Patel A, Scott AJ, Patel K, Thursz M, Lemoine M. Prevalence and risk factors of nonalcoholic fatty liver disease in HIV‐monoinfection. AIDS 2017;31:1621‐1632.
    1. Lui G, Wong VW‐S, Wong Gl‐H, Chu WC‐W, Wong C‐K, Yung IMH, et al. Liver fibrosis and fatty liver in Asian HIV‐infected patients. Aliment Pharmacol Ther 2016;44:411‐421.
    1. Vodkin I, Valasek MA, Bettencourt R, Cachay E, Loomba R. Clinical, biochemical and histological differences between HIV‐associated NAFLD and primary NAFLD: a case‐control study. Aliment Pharmacol Ther 2015;41:368‐378.
    1. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease—meta‐analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016;64:73‐84.
    1. Mohammed SS, Aghdassi E, Salit IE, Avand G, Sherman M, Guindi M, et al. HIV‐positive patients with nonalcoholic fatty liver disease have a lower body mass index and are more physically active than HIV‐negative patients. J Acquir Immune Defic Syndr 2007;45:432‐438.
    1. Kusminski CM, Bickel PE, Scherer PE. Targeting adipose tissue in the treatment of obesity‐associated diabetes. Nat Rev Drug Discov 2016;15:639‐660.
    1. McComsey GA, Kitch D, Sax PE, Tebas P, Tierney C, Jahed NC, et al. Peripheral and central fat changes in subjects randomized to abacavir‐lamivudine or tenofovir‐emtricitabine with atazanavir‐ritonavir or efavirenz: ACTG Study A5224s. Clin Infect Dis 2011;53:185‐196.
    1. Koethe JR, Lagathu C, Lake JE, Domingo P, Calmy A, Falutz J, et al. HIV and antiretroviral therapy‐related fat alterations. Nat Rev Dis Primers 2020;6:48.
    1. Gallego‐Escuredo JM, Villarroya J, Domingo P, Targarona EM, Alegre M, Domingo JC, et al. Differentially altered molecular signature of visceral adipose tissue in HIV‐1‐associated lipodystrophy. J Acquir Immune Defic Syndr 2013;64:142‐148.
    1. Goodpaster BH, Kelley DE, Thaete FL, He J, Ross R. Skeletal muscle attenuation determined by computed tomography is associated with skeletal muscle lipid content. J Appl Physiol 1985;2000:104‐110.
    1. Kodama Y, Ng CS, Wu TT, Ayers GD, Curley SA, Abdalla EK, et al. Comparison of CT methods for determining the fat content of the liver. AJR Am J Roentgenol 2007;188:1307‐1312.
    1. Kim D, Chung GE, Kwak M‐S, Seo HB, Kang JH, Kim W, et al. Body fat distribution and risk of incident and regressed nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2016;14:e134.
    1. Chung GE, Kim D, Kwark MS, Kim W, Yim JY, Kim YJ, et al. Visceral adipose tissue area as an independent risk factor for elevated liver enzyme in nonalcoholic fatty liver disease. Medicine (Baltimore) 2015;94:e573.
    1. Côté JA, Nazare JA, Nadeau M, Leboeuf M, Blackburn L, Després JP, et al. Computed tomography‐measured adipose tissue attenuation and area both predict adipocyte size and cardiometabolic risk in women. Adipocyte 2016;5:35‐42.
    1. Verboven K, Wouters K, Gaens K, Hansen D, Bijnen M, Wetzels S, et al. Abdominal subcutaneous and visceral adipocyte size, lipolysis and inflammation relate to insulin resistance in male obese humans. Sci Rep 2018;8:4677.
    1. Polyzos SA, Perakakis N, Mantzoros CS. Fatty liver in lipodystrophy: a review with a focus on therapeutic perspectives of adiponectin and/or leptin replacement. Metabolism 2019;96:66‐82.
    1. Alexander RW, Harrell DB. Autologous fat grafting: use of closed syringe microcannula system for enhanced autologous structural grafting. Clin Cosmet Investig Dermatol 2013;6:91‐102.
    1. VanWagner LB, Ning H, Lewis CE, Shay CM, Wilkins J, Carr JJ, et al. Associations between nonalcoholic fatty liver disease and subclinical atherosclerosis in middle‐aged adults: the Coronary Artery Risk Development in Young Adults Study. Atherosclerosis 2014;235:599‐605.
    1. Carr JJ, Nelson JC, Wong ND, McNitt‐Gray M, Arad Y, Jacobs DR, et al. Calcified coronary artery plaque measurement with cardiac CT in population‐based studies: standardized protocol of Multi‐Ethnic Study of Atherosclerosis (MESA) and Coronary Artery Risk Development in Young Adults (CARDIA) study. Radiology 2005;234:35‐43.
    1. Terry JG, Shay CM, Schreiner PJ, Jacobs DR, Sanchez OA, Reis JP, et al. Intermuscular adipose tissue and subclinical coronary artery calcification in midlife: the CARDIA Study (Coronary Artery Risk Development in Young Adults). Arterioscler Thromb Vasc Biol 2017;37:2370‐2378.
    1. Chung H, Cobzas D, Lieffers JR, Birdsell L, Baracos V. Automated segmentation of muscle and adipose tissue on CT images for human body composition analysis. In: Proceedings of the International Society for Optical Engineering 7261, San Diego, California; 2009:197‐204.
    1. Miljkovic I, Kuipers AL, Cvejkus RK, Carr JJ, Terry JG, Thyagarajan B, et al. Hepatic and skeletal muscle adiposity are associated with diabetes independent of visceral adiposity in nonobese African‐Caribbean men. Metab Syndr Relat Disord 2020;18:275‐283.
    1. Alman AC, Jacobs DR, Lewis CE, Snell‐Bergeon JK, Carnethon MR, Terry JG, et al. Higher pericardial adiposity is associated with prevalent diabetes: the Coronary Artery Risk Development in Young Adults study. Nutr Metab Cardiovasc Dis 2016;26:326‐332.
    1. Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 2003;13:2498‐2504.
    1. National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention Division of HIV/AIDS Prevention . Estimated HIV incidence and prevalence in the United States, 2010‐2016. In: HIV Surveillance Supplemental Report 2019, Volume 24.
    1. Rasouli N, Molavi B, Elbein SC, Kern PA. Ectopic fat accumulation and metabolic syndrome. Diabetes Obes Metab 2007;9:1‐10.
    1. Bailin SS, Gabriel CL, Wanjalla CN, Koethe JR. Obesity and weight gain in persons with HIV. Curr HIV/AIDS Rep 2020;17:138‐150.
    1. Bacchetti P, Gripshover B, Grunfeld C, Heymsfield S, McCreath H, Osmond D, et al. Fat distribution in men with HIV infection. J Acquir Immune Defic Syndr 2005;40:121‐131.
    1. Lee JJ, Pedley A, Hoffmann U, Massaro JM, Fox CS. Association of changes in abdominal fat quantity and quality with incident cardiovascular disease risk factors. J Am Coll Cardiol 2016;68:1509‐1521.
    1. Lee JJ, Britton KA, Pedley A, Massaro JM, Speliotes EK, Murabito JM, et al. Adipose tissue depots and their cross‐sectional associations with circulating biomarkers of metabolic regulation. J Am Heart Assoc 2016;5:e002936.
    1. Couturier J, Agarwal N, Nehete PN, Baze WB, Barry MA, Jagannadha Sastry K, et al. Infectious SIV resides in adipose tissue and induces metabolic defects in chronically infected rhesus macaques. Retrovirology 2016;13:30.
    1. Giralt M, Domingo P, Guallar JP, Rodriguez de la Concepcion ML, Alegre M, Domingo JC, et al. HIV‐1 infection alters gene expression in adipose tissue, which contributes to HIV‐ 1/HAART‐associated lipodystrophy. Antivir Ther 2006;11:729‐740.
    1. Gorwood J, Bourgeois C, Mantecon M, Atlan M, Pourcher V, Pourcher G, et al. Impact of HIV/simian immunodeficiency virus infection and viral proteins on adipose tissue fibrosis and adipogenesis. AIDS 2019;33:953‐964.
    1. Caron M, Auclair M, Lagathu C, Lombes A, Walker UA, Kornprobst M, et al. The HIV‐1 nucleoside reverse transcriptase inhibitors stavudine and zidovudine alter adipocyte functions in vitro. AIDS 2004;18:2127‐2136.
    1. Rudich A, Ben‐Romano R, Etzion S, Bashan N. Cellular mechanisms of insulin resistance, lipodystrophy and atherosclerosis induced by HIV protease inhibitors. Acta Physiol Scand 2005;183:75‐88.
    1. Gorwood J, Bourgeois C, Pourcher V, Pourcher G, Charlotte F, Mantecon M, et al. The integrase inhibitors dolutegravir and raltegravir exert pro‐adipogenic and profibrotic effects and induce insulin resistance in human/simian adipose tissue and human adipocytes. Clin Infect Dis 2020. Mar 13. 10.1093/cid/ciaa259. [Epub ahead of print]
    1. Bastard J‐P, Caron M, Vidal H, Jan V, Auclair M, Vigouroux C, et al. Association between altered expression of adipogenic factor SREBP1 in lipoatrophic adipose tissue from HIV‐1‐infected patients and abnormal adipocyte differentiation and insulin resistance. Lancet 2002;359:1026‐1031.
    1. Lake JE, Moser C, Johnston L, Magyar C, Nelson SD, Erlandson KM, et al. CT fat density accurately reflects histologic fat quality in adults with HIV on and off antiretroviral therapy. J Clin Endocrinol Metab 2019;104:4857‐4864.
    1. Gelpi M, Knudsen AD, Larsen KB, Mocroft A, Lebech A‐M, Lindegaard B, et al. Long‐lasting alterations in adipose tissue density and adiponectin production in people living with HIV after thymidine analogues exposure. BMC Infect Dis 2019;19:708.
    1. Lake JE, Debroy P, Ng D, Erlandson KM, Kingsley LA, Palella FJ, et al. Associations between subcutaneous fat density and systemic inflammation differ by HIV serostatus and are independent of fat quantity. Eur J Endocrinol 2019;181:451‐459.
    1. Debroy P, Lake JE, Moser C, Olefsky M, Erlandson KM, Scherzinger A, et al. Antiretroviral therapy initiation is associated with decreased visceral and subcutaneous adipose tissue density in people living with HIV. Clin Infect Dis 2020. Feb 28. 10.1093/cid/ciaa196. [Epub ahead of print]
    1. Stern JH, Rutkowski JM, Scherer PE. Adiponectin, leptin, and fatty acids in the maintenance of metabolic homeostasis through adipose tissue crosstalk. Cell Metab 2016;23:770‐784.
    1. Mead JR, Irvine SA, Ramji DP. Lipoprotein lipase: structure, function, regulation, and role in disease. J Mol Med (Berl) 2002;80:753‐769.
    1. Song Z, Xiaoli AM, Yang F. Regulation and metabolic significance of de novo lipogenesis in adipose tissues. Nutrients 2018;10:1383.
    1. Guardiola M, Echeverria P, González M, Vallvé JC, Puig J, Clotet B, et al. Polymorphisms in LPL, CETP, and HL protect HIV‐infected patients from atherogenic dyslipidemia in an allele‐dose‐dependent manner. AIDS Res Hum Retroviruses 2015;31:882‐888.
    1. Rose H, Hoy J, Woolley I, Tchoua U, Bukrinsky M, Dart A, et al. HIV infection and high density lipoprotein metabolism. Atherosclerosis 2008;199:79‐86.
    1. Kulkarni MM, Ratcliff AN, Bhat M, Alwarawrah Y, Hughes P, Arcos J, et al. Cellular fatty acid synthase is required for late stages of HIV‐1 replication. Retrovirology 2017;14:45.

Source: PubMed

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