Genetic regulation of TF expression in adipose tissue plays a novel role in regulating SI.
High tissue iron levels are a risk factor for multiple chronic diseases including type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD). To investigate causal relationships and underlying mechanisms, we used an established NAFLD model—mice fed a high fat diet with supplemental fructose in the water (“fast food”, FF). Iron did not affect excess hepatic triglyceride accumulation in the mice on FF, and FF did not affect iron accumulation compared to normal chow. Mice on low iron are protected from worsening of markers for non-alcoholic steatohepatitis (NASH), including serum transaminases and fibrotic gene transcript levels. These occurred prior to the onset of significant insulin resistance or changes in adipokines. Transcriptome sequencing revealed the major effects of iron to be on signaling by the transforming growth factor beta (TGF-β) pathway, a known mechanistic factor in NASH. High iron increased fibrotic gene expression in vitro, demonstrating that the effect of dietary iron on NASH is direct. Conclusion: A lower tissue iron level prevents accelerated progression of NAFLD to NASH, suggesting a possible therapeutic strategy in humans with the disease.
Iron is an important micronutrient involved in several metabolic processes, and excessive iron is a risk factor for insulin resistance (IR) and diabetes. To define the genetic regulation of iron metabolism and its role in IR, we used gene expression, genotype, and insulin sensitivity data from an African American cohort (AAGMEx, N=256). Among the genes in a manually curated list of 62 transcripts representing iron homeostasis genes, expression of 32 in adipose tissue showed significant correlation with SI (p<0.01). The expression levels of transferrin (TF, β= 0.29, p=7.84 x 10-6) and ferritin heavy chain 1 (FTH1, β= -1.2, p=3.75 x 10-13) in adipose tissue were the most positively and negatively associated with SI, respectively. Observations were replicated in independent adipose tissue data sets from individuals of European ancestry (ARCA, N=99; METSIM, N=720). Among these SI-associated transcripts, the strongest cis-regulatory genetic variant (cis-eSNP) was for TF (rs6785596, β= 0.962, p=7.84 x 10-18) in adipose, but not in muscle or liver. To identify the role of TF in adipocytes, we downregulated its expression in a human adipocyte cell model (SGBS). Gene specific shRNA knockdown of TF caused differential expression (log2FC +/-0.4, probability>70%) of 465 genes, involved in mitochondrial function (CPT1B, UCP2), glucose transport (GLUT4), Wnt-pathway/insulin sensitivity (SFRP4, SFRP1), chemokine activity/cell-cell interaction (CXCL1, CXCL12, ICAM1), and genes with possible roles in obesity (CES1, RARRES2). Knockdown of TF mRNA in differentiated SGBS cells impaired mitochondrial respiration (49±10% reduction of maximal oxygen consumption rate) and caused a 34±4% reduction in maximal insulin-stimulated glucose uptake (p<0.05). In summary, genetic regulation of transferrin expression in adipose tissue plays a novel role in regulating insulin sensitivity. Disclosure D. McClain: None. N.K. Sharma: None. F. Lorenzo: None. S. Jain: None. C.D. Langefeld: None. M.E. Comeau: None. L. Salaye: None. S.K. Das: None.
Iron is a risk factor for type 2 diabetes, but its relationship to other aspects of metabolic syndrome is less clear. To investigate iron’s relation to nonalcoholic steatohepatitis (NASH), mice were fed a “fast food” (FF)-diet (40% energy as fat, 12% SFA, 0.2% cholesterol, and 18.9 g/L glucose and 23.1 g/L fructose in their drinking water) for 10 or 24 weeks. The diets contained either 4 (low iron, LI), 35 (normal iron, NI) or 2000mg iron/kg chow (high iron, HI). HOMA-IR values were 2.2-fold higher (p<0.001) in the FF-groups at 10 weeks, but did not increase further with HI (1.48-fold, p=0.5). At 10 weeks all groups had similar glucose excursions during glucose and pyruvate tolerance testing. There was no significant difference in IP-GTT or IP-PTT area under the glucose curve. Liver triglycerides (TG) were significantly increased by FF (4.2-fold, p<0.01) but not iron at 10 weeks. The effect of FF was greater at 24 weeks (22.4 fold p<0.001), and at 24 weeks iron further increased liver TG (3.3 fold HIFF vs. LIFF, p<0.001). A marker of liver injury (ALT) increased 10.3-fold (p<0.001) on the HIFF diet compared to LI normal chow, but only 3.2-fold (p<0.05) on LIFF. The fibrotic gene collagen1alpha increased 14.3-fold (p<0.001) in HIFF but not at all (0.8-fold) on LIFF compared to LI normal chow. Similar protection was afforded by the LI diet to increases in expression of the inflammatory genes TGF-beta and TNF-alpha seen in HIFF. RNA sequencing data revealed transcriptional regulation of a large family of fat metabolic genes by FF, whereas only the TGF-beta signaling pathway was significantly altered by iron content. We conclude that dietary iron restriction can protect from NASH induced by a high-fat and -carbohydrate diet. A likely candidate mechanism is through a known mediator of hepatic fibrosis, TGF-beta. Disclosure L. Salaye: None. I. Bychkova: None. F. Lorenzo: None. S.T. Sink: None. D. McClain: None.
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