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A lipidomic human population and translational feeding study of hepatic steatosis and de novo lipogenesis (Human plasma assay)

ABSTRACT: Background: Diet is a major contributor to metabolic disease risk, but there is controversy as to whether increased incidences of diseases such as non-alcoholic fatty liver disease arise from consumption of saturated fats or free sugars. Our aims were to investigate whether a sub-set of TAGs were associated with hepatic steatosis and whether they arise from de novo lipogenesis (DNL) from the consumption of carbohydrates.

Results: We conducted direct infusion mass spectrometry of lipids in plasma to study the association between specific triacylglycerols (TAGs) and hepatic steatosis assessed by ultrasound and fatty liver index in volunteers from the UK-based Fenland Study (n=1507), and evaluated clustering of TAGs in the National Survey of Health and Development UK cohort (n=1701). TAGs formed 3 clusters, with those TAGs containing saturated and monounsaturated fatty acids with 16-18 carbons being specifically associated with hepatic steatosis. These TAGs were associated with higher consumption of carbohydrate and saturated fat, hepatic steatosis, and variations in the gene for protein phosphatase 1, regulatory subunit 3b (PPP1R3B), which in part regulates glycogen synthesis. DNL was measured in hyperphagic ob/ob mice, mice on a Western diet (high in fat and free sugar) and in healthy humans using stable isotope techniques following high carbohydrate meals, demonstrating the rate of DNL correlates with increased synthesis of this cluster of TAGs. Furthermore, these TAGs were increased in plasma from patients with biopsy-confirmed steatosis.

Conclusion: A sub-set of TAGs are associated with hepatic steatosis, even when correcting for common confounding factors. We suggest that hepatic steatosis risk in Western populations is in part driven by increased DNL following carbohydrate rich meals.

The protocols and data of the murine study of de novo lipogenesis are included in the study MTBLS614.

Linked Studies: MTBLS614

INSTRUMENT(S): Direct Infusion MS - Alternating (DI-MS (Alternating))

SUBMITTER: Jules Griffin

PROVIDER: MTBLS616 | MetaboLights | 2018-03-13

REPOSITORIES: MetaboLights

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Project description:Background: Diet is a major contributor to metabolic disease risk, but there is controversy as to whether increased incidences of diseases such as non-alcoholic fatty liver disease arise from consumption of saturated fats or free sugars. Our aims were to investigate whether a sub-set of TAGs were associated with hepatic steatosis and whether they arise from de novo lipogenesis (DNL) from the consumption of carbohydrates. Results: We conducted direct infusion mass spectrometry of lipids in plasma to study the association between specific triacylglycerols (TAGs) and hepatic steatosis assessed by ultrasound and fatty liver index in volunteers from the UK-based Fenland Study (n=1507), and evaluated clustering of TAGs in the National Survey of Health and Development UK cohort (n=1701). TAGs formed 3 clusters, with those TAGs containing saturated and monounsaturated fatty acids with 16-18 carbons being specifically associated with hepatic steatosis. These TAGs were associated with higher consumption of carbohydrate and saturated fat, hepatic steatosis, and variations in the gene for protein phosphatase 1, regulatory subunit 3b (PPP1R3B), which in part regulates glycogen synthesis. DNL was measured in hyperphagic ob/ob mice, mice on a Western diet (high in fat and free sugar) and in healthy humans using stable isotope techniques following high carbohydrate meals, demonstrating the rate of DNL correlates with increased synthesis of this cluster of TAGs. Furthermore, these TAGs were increased in plasma from patients with biopsy-confirmed steatosis. Conclusion: A sub-set of TAGs are associated with hepatic steatosis, even when correcting for common confounding factors. We suggest that hepatic steatosis risk in Western populations is in part driven by increased DNL following carbohydrate rich meals. The protocols and data of the human carbohydrate feeding study in healthy volunteers are reported in the study MTBLS616. Linked Studies: <a href='https://www.ebi.ac.uk/metabolights/MTBLS616' target='_blank'>MTBLS616</a>

Project description:Caloric Restriction in Leptin Deficiency Worsens Myocardial Steatosis: Failure to Upregulate PPAR gamma and Thermogenic Glyecrolipid/Fatty Acid Cycling Growing evidence supports an anti-lipotoxic role for leptin in preventing inappropriate peripheral tissue lipid deposition. Obese, leptin deficient ob/ob mice develop left ventricular (LV) hypertrophy and myocardial steatosis with increased apoptosis and decreased longevity. Here we investigated the cardiac effects of caloric restriction in leptin deficiency. Echocardiography was performed on C57Bl/6 wild-type mice (WT) and 7-month-old ob/ob mice fed ad lib, leptin-repleted (LR-ob/ob), or calorie-restricted (CR-ob/ob) for four weeks. Ventricular tissue was examined by electron microscopy (EM), mitochondrial coupling assay, and microarray expression profiling. LR and CR-ob/ob mice showed decreased body weight, heart weight, and LV wall thickness compared to ad lib ob/ob mice. LV fractional shortening was decreased in ad lib ob/ob mice, but restored to WT levels in LR and CR groups. However, EM revealed severe cardiac steatosis in the CR-ob/ob group compared to only moderate steatosis in ad lib ob/ob . Despite marked cardiac steatosis, CR (like LR) restored mitochondrial coupling to WT levels. CR up-regulated genes associated with oxidative stress and cell death, changes suggestive of cardiac lipotoxicity. LR, but not CR was shown to induce core genes involved in glycerolipid/free fatty acid cycling, a highly thermogenic pathway that can reduce intracellular lipid stores. LR, but not CR up-regulated and restored PGC1 and PPARto wild type levels; CR paradoxically further suppressed cardiac PPAR. Thus, leptin is essential in protecting the heart from lipotoxicity, and the inability to up-regulate the thermogenic glycerolipid/free fatty acid cycling pathway may impair the response of leptin deficient animals to the lipotoxic stress of calorie restriction. 6 month aged ob/ob mice were either leptin repleted with osmotic mini-pumps, calorie restricted to match the caloric intake of the leptin repleted mice, or fed ad lib for one month. 6-8 month C57Bl/6J mice were aged to serve as controls.

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A lipidomic human population and translational feeding study of hepatic steatosis and de novo lipogenesis (Human plasma assay)

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