{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T15:17:57Z","timestamp":1792250277647,"version":"4.4.0"},"reference-count":26,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2017,2,25]],"date-time":"2017-02-25T00:00:00Z","timestamp":1487980800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1"},{"start":{"date-parts":[[2017,2,25]],"date-time":"2017-02-25T00:00:00Z","timestamp":1487980800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2017,4]]},"abstract":"<jats:p>The cut\u2010off point of intrahepatic triglyceride (IHTG) content to define nonalcoholic fatty liver disease (NAFLD) by proton magnetic resonance spectroscopy (<jats:sup>1<\/jats:sup>H\u2010MRS) was established based on the 95th percentile in a group of healthy individuals (i.e., \u22655.56%). Whether this threshold correlates with metabolic and histological changes and whether a further accumulation of IHTG is associated with worsening of these parameters has not been properly assessed in a large cohort of patients. In this cross\u2010sectional study, 352 subjects were carefully characterized with the following studies: liver <jats:sup>1<\/jats:sup>H\u2010MRS; euglycemic insulin clamp with measurement of glucose turnover; oral glucose tolerance test; and a liver biopsy. Hepatic insulin sensitivity (suppression of endogenous glucose production by insulin) was affected early on after IHTG content was \u223c1.5% and remained uniformly impaired (\u223c40%\u201045%), regardless of further IHTG accumulation. Skeletal muscle insulin sensitivity showed a gradual impairment at low degrees of IHTG accumulation, but remained unchanged after IHTG content reached the \u223c6 \u00b1 2% threshold. A similar pattern was observed for metabolic changes typically associated with NAFLD, such as hypertriglyceridemia and low high\u2010density lipoprotein cholesterol (HDL\u2010C). In contrast, adipose tissue insulin sensitivity (suppression of free fatty acids by insulin) showed a continuous worsening across the spectrum of IHTG accumulation in NAFLD (r = \u20130.38; <jats:italic toggle=\"yes\">P<\/jats:italic> &lt; 0.001). Histological severity of liver disease (inflammation, ballooning, and fibrosis) was not associated with the amount of IHTG content. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: IHTG accumulation is strongly associated with adipose tissue insulin resistance (IR), supporting the current theory of lipotoxicity as a driver of IHTG accumulation. Once IHTG accumulation reaches \u223c6 \u00b1 2%, skeletal muscle IR, hypertriglyceridemia, and low HDL\u2010C become fully established. Histological activity appears to have an early threshold and is not significantly influenced by increasing amounts of IHTG accumulation. (H<jats:sc>epatology<\/jats:sc> 2017;65:1132\u20101144).<\/jats:p>","DOI":"10.1002\/hep.28985","type":"journal-article","created":{"date-parts":[[2016,12,17]],"date-time":"2016-12-17T14:10:54Z","timestamp":1481983854000},"page":"1132-1144","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":276,"title":["Metabolic and histological implications of intrahepatic triglyceride content in nonalcoholic fatty liver disease"],"prefix":"10.1097","volume":"65","author":[{"given":"Fernando","family":"Bril","sequence":"first","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism,University of Florida,Gainesville,FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Barb","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism,University of Florida,Gainesville,FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Portillo\u2010Sanchez","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism,University of Florida,Gainesville,FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane","family":"Biernacki","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism,University of Florida,Gainesville,FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romina","family":"Lomonaco","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism,University of Florida,Gainesville,FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amitabh","family":"Suman","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology and Nutrition,Malcom Randall VAMC,Gainesville,FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle H.","family":"Weber","sequence":"additional","affiliation":[{"name":"Department of Pathology,Malcom Randall VAMC,Gainesville,FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey T.","family":"Budd","sequence":"additional","affiliation":[{"name":"Department of Medicine,University of Florida,Gainesville,FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria E.","family":"Lupi","sequence":"additional","affiliation":[{"name":"Division of Family Medicine,University of Florida,Gainesville,FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth","family":"Cusi","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism,University of Florida,Gainesville,FL"},{"name":"Division of Endocrinology, Diabetes and Metabolism,Malcom Randall VAMC,Gainesville,FL"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2017,2,25]]},"reference":[{"key":"hep28985-bib-0001-20241017","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1007\/s00125-016-3902-y","article-title":"EASL\u2010EASD\u2010EASO Clinical Practice Guidelines for the management of non\u2010alcoholic fatty liver disease","volume":"59","year":"2016","journal-title":"Diabetologia"},{"key":"hep28985-bib-0002-20241017","doi-asserted-by":"crossref","first-page":"1592","DOI":"10.1053\/j.gastro.2012.04.001","article-title":"The diagnosis and management of non\u2010alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology","volume":"142","year":"2012","journal-title":"Gastroenterology"},{"key":"hep28985-bib-0003-20241017","doi-asserted-by":"crossref","first-page":"E462","DOI":"10.1152\/ajpendo.00064.2004","article-title":"Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population","volume":"288","year":"2005","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"hep28985-bib-0004-20241017","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1210\/jc.2015-3111","article-title":"Hepatic steatosis and insulin resistance, but not steatohepatitis, promote atherogenic dyslipidemia in NAFLD","volume":"101","year":"2016","journal-title":"J Clin Endocrinol Metab"},{"key":"hep28985-bib-0005-20241017","doi-asserted-by":"crossref","first-page":"2139","DOI":"10.1111\/liv.12840","article-title":"Clinical value of liver ultrasound for the diagnosis of nonalcoholic fatty liver disease in overweight and obese patients","volume":"35","year":"2015","journal-title":"Liver Int"},{"key":"hep28985-bib-0006-20241017","doi-asserted-by":"crossref","first-page":"2297","DOI":"10.1056\/NEJMoa060326","article-title":"A placebo\u2010controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis","volume":"355","year":"2006","journal-title":"N Engl J Med"},{"key":"hep28985-bib-0007-20241017","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1111\/j.1365-2036.2012.05121.x","article-title":"Correlation between liver histology and novel magnetic resonance imaging in adult patients with non\u2010alcoholic fatty liver disease\u2014MRI accurately quantifies hepatic steatosis in NAFLD","volume":"36","year":"2012","journal-title":"Aliment Pharmacol Ther"},{"key":"hep28985-bib-0008-20241017","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1002\/hep.24483","article-title":"Role of ethnicity in overweight and obese patients with nonalcoholic steatohepatitis","volume":"54","year":"2011","journal-title":"Hepatology"},{"key":"hep28985-bib-0009-20241017","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1136\/jim-2015-000019","article-title":"Plasma thyroid hormone concentration is associated with hepatic triglyceride content in patients with type 2 diabetes","volume":"64","year":"2016","journal-title":"J Investig Med"},{"key":"hep28985-bib-0010-20241017","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/j.jhep.2014.08.040","article-title":"Relationship of vitamin D with insulin resistance and disease severity in non\u2010alcoholic steatohepatitis","volume":"62","year":"2015","journal-title":"J Hepatol"},{"key":"hep28985-bib-0011-20241017","doi-asserted-by":"crossref","first-page":"2178","DOI":"10.1002\/hep.26988","article-title":"Relationship between disease severity, hyperinsulinemia, and impaired insulin clearance in patients with nonalcoholic steatohepatitis","volume":"59","year":"2014","journal-title":"Hepatology"},{"key":"hep28985-bib-0012-20241017","doi-asserted-by":"crossref","first-page":"632","DOI":"10.2337\/dc15-1876","article-title":"Metabolic impact of nonalcoholic steatohepatitis in obese patients with type 2 diabetes","volume":"39","year":"2016","journal-title":"Diabetes Care"},{"issue":"Suppl 1","key":"hep28985-bib-0013-20241017","first-page":"S4","article-title":"Standards of Medical Care in Diabetes\u20102016: Summary of Revisions","volume":"39","year":"2016","journal-title":"Diabetes Care"},{"key":"hep28985-bib-0014-20241017","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1097\/RMR.0b013e3181c422f1","article-title":"Review of magnetic resonance spectroscopy in the liver and the pancreas","volume":"20","year":"2009","journal-title":"Top Magn Reson Imaging"},{"key":"hep28985-bib-0015-20241017","doi-asserted-by":"crossref","first-page":"2461","DOI":"10.2337\/diabetes.52.10.2461","article-title":"A sustained increase in plasma free fatty acids impairs insulin secretion in nondiabetic subjects genetically predisposed to develop type 2 diabetes","volume":"52","year":"2003","journal-title":"Diabetes"},{"key":"hep28985-bib-0016-20241017","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1002\/hep.24376","article-title":"Endpoints and clinical trial design for nonalcoholic steatohepatitis","volume":"54","year":"2011","journal-title":"Hepatology"},{"key":"hep28985-bib-0017-20241017","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1055\/s-0032-1306421","article-title":"Nonalcoholic fatty liver disease: pathologic patterns and biopsy evaluation in clinical research","volume":"32","year":"2012","journal-title":"Semin Liver Dis"},{"key":"hep28985-bib-0018-20241017","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.1016\/j.cgh.2015.01.027","article-title":"Association between quantity of liver fat and cardiovascular risk in patients with nonalcoholic fatty liver disease independent of nonalcoholic steatohepatitis","volume":"13","year":"2015","journal-title":"Clin Gastroenterol Hepatol"},{"key":"hep28985-bib-0019-20241017","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1053\/j.gastro.2012.02.003","article-title":"Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications","volume":"142","year":"2012","journal-title":"Gastroenterology"},{"key":"hep28985-bib-0020-20241017","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1002\/hep.23719","article-title":"Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites","volume":"52","year":"2010","journal-title":"Hepatology"},{"key":"hep28985-bib-0021-20241017","doi-asserted-by":"crossref","first-page":"305","DOI":"10.7326\/M15-1774","article-title":"Long\u2010term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial","volume":"165","year":"2016","journal-title":"Ann Intern Med"},{"key":"hep28985-bib-0022-20241017","doi-asserted-by":"crossref","first-page":"1578","DOI":"10.1210\/jc.2014-3794","article-title":"Effect of vildagliptin on hepatic steatosis","volume":"100","year":"2015","journal-title":"J Clin Endocrinol Metab"},{"key":"hep28985-bib-0023-20241017","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1002\/hep.27647","article-title":"Ezetimibe for the treatment of nonalcoholic steatohepatitis: assessment by novel magnetic resonance imaging and magnetic resonance elastography in a randomized trial (MOZART trial)","volume":"61","year":"2015","journal-title":"Hepatology"},{"key":"hep28985-bib-0024-20241017","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.2337\/dc14-2548","article-title":"Effects of insulin glargine and liraglutide therapy on liver fat as measured by magnetic resonance in patients with type 2 diabetes: a randomized trial","volume":"38","year":"2015","journal-title":"Diabetes Care"},{"key":"hep28985-bib-0025-20241017","doi-asserted-by":"crossref","first-page":"2341","DOI":"10.1111\/liv.12869","article-title":"Response to do ultrasonographic semiquantitative indices predict histological changes in NASH irrespective of steatosis extent?","volume":"35","year":"2015","journal-title":"Liver Int"},{"key":"hep28985-bib-0026-20241017","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1053\/j.gastro.2008.03.078","article-title":"Rosiglitazone for nonalcoholic steatohepatitis: one\u2010year results of the randomized placebo\u2010controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial","volume":"135","year":"2008","journal-title":"Gastroenterology"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.28985","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-201704000-00012","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,18]],"date-time":"2024-10-18T00:09:01Z","timestamp":1729210141000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-201704000-00012"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,2,25]]},"references-count":26,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2017]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.28985","relation":{},"ISSN":["0270-9139","1527-3350"],"issn-type":[{"value":"0270-9139","type":"print"},{"value":"1527-3350","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,2,25]]},"assertion":[{"value":"2016-08-29","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-11-30","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}