Hepatic Deficiency in Transcriptional Cofactor TBL1 Promotes Liver Steatosis and Hypertriglyceridemia

Kulozik, Philipp; Jones, Allan; Mattijssen, Frits; Rose, Adam J.; Reimann, Anja; Strzoda, Daniela; Kleinsorg, Stefan; Raupp, Christina; Kleinschmidt, Jürgen A.; Müller‐Decker, Karin; Wahli, Walter; Sticht, Carsten; Gretz, Norbert; Loeffelholz, Christian von; Stockmann, Martin; Pfeiffer, Andreas F. H.; Stöhr, Sigrid; Dallinga‐Thie, Geesje M.; Nawroth, Peter P.; Díaz, Mauricio Berriel; Herzig, Stephan

doi:10.1016/j.cmet.2011.02.011

Cited by 49 publications

(49 citation statements)

References 45 publications

(50 reference statements)

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“…To shed light on the potentially underlying mechanism of amorfrutin-based prevention of liver disorders in HFD mice, we determined gene expression profiles in liver tissue. As reported recently, accumulation of triglycerides in the liver is-although the exact molecular mechanism is still unclear-causally linked to decreased expression of transducin beta-like 1 (Tbl1), a transcriptional cofactor of PPARα, which is the master regulator of fatty acid oxidation (33). Consistent with previous results, Tbl1 expression negatively correlated with liver steatosis (SI Appendix, Fig.…”

Section: Amorfrutins Inhibit Hfd-induced Pparγ Ser273 Phosphorylation Insupporting

confidence: 79%

Amorfrutins are potent antidiabetic dietary natural products

Weidner

Groot

Prasad

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

175

251

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Given worldwide increases in the incidence of obesity and type 2 diabetes, new strategies for preventing and treating metabolic diseases are needed. The nuclear receptor PPARγ (peroxisome proliferator-activated receptor gamma) plays a central role in lipid and glucose metabolism; however, current PPARγ-targeting drugs are characterized by undesirable side effects. Natural products from edible biomaterial provide a structurally diverse resource to alleviate complex disorders via tailored nutritional intervention. We identified a family of natural products, the amorfrutins, from edible parts of two legumes, Glycyrrhiza foetida and Amorpha fruticosa, as structurally new and powerful antidiabetics with unprecedented effects for a dietary molecule. Amorfrutins bind to and activate PPARγ, which results in selective gene expression and physiological profiles markedly different from activation by current synthetic PPARγ drugs. In diet-induced obese and db/db mice, amorfrutin treatment strongly improves insulin resistance and other metabolic and inflammatory parameters without concomitant increase of fat storage or other unwanted side effects such as hepatoxicity. These results show that selective PPARγ-activation by diet-derived ligands may constitute a promising approach to combat metabolic disease.nuclear receptors | nutrition | compound screening | organic synthesis | x-ray structure

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Section: Amorfrutins Inhibit Hfd-induced Pparγ Ser273 Phosphorylation Insupporting

confidence: 79%

Amorfrutins are potent antidiabetic dietary natural products

Weidner

Groot

Prasad

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

175

251

View full text Add to dashboard Cite

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“…Thus, we employed an adeno-associated virus (AAV) delivery system allowing the expression of TSC22D4-directed miRNAs specifically in liver parenchymal cells but not in other liver cell types for a period of several months13. Six weeks after AAV-mediated miRNA delivery, wild-type mice with hepatocyte-specific TSC22D4 deficiency (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Control of diabetic hyperglycaemia and insulin resistance through TSC22D4

et al. 2016

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Obesity-related insulin resistance represents the core component of the metabolic syndrome, promoting glucose intolerance, pancreatic beta cell failure and type 2 diabetes. Efficient and safe insulin sensitization and glucose control remain critical therapeutic aims to prevent diabetic late complications Here, we identify transforming growth factor beta-like stimulated clone (TSC) 22 D4 as a molecular determinant of insulin signalling and glucose handling. Hepatic TSC22D4 inhibition both prevents and reverses hyperglycaemia, glucose intolerance and insulin resistance in diabetes mouse models. TSC22D4 exerts its effects on systemic glucose homeostasis—at least in part—through the direct transcriptional regulation of the small secretory protein lipocalin 13 (LCN13). Human diabetic patients display elevated hepatic TSC22D4 expression, which correlates with decreased insulin sensitivity, hyperglycaemia and LCN13 serum levels. Our results establish TSC22D4 as a checkpoint in systemic glucose metabolism in both mice and humans, and propose TSC22D4 inhibition as an insulin sensitizing option in diabetes therapy.

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“…Hepatocyte-specific overexpression of PGC-1β increases the expression of β oxidative genes and protects PGC-1β transgenic mice from diet-induced steatosis (12). Knockdown of TBL1 or its partner TBLR1 in the liver inhibits PPARα activity, decreases β oxidation and ketogenesis, and promotes hepatic steatosis (117). …”

Section: Liver Fatty Acid Metabolismmentioning

confidence: 99%

Energy Metabolism in the Liver

Rui

2014

Comprehensive Physiology

1,500

1,162

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The liver is an essential metabolic organ, and its metabolic activity is tightly controlled by insulin and other metabolic hormones. Glucose is metabolized into pyruvate through glycolysis in the cytoplasm, and pyruvate is completely oxidized to generate ATP through the TCA cycle and oxidative phosphorylation in the mitochondria. In the fed state, glycolytic products are used to synthesize fatty acids through de novo lipogenesis. Long-chain fatty acids are incorporated into triacylglycerol, phospholipids, and cholesterol esters in hepatocytes, and these complex lipids are stored in lipid droplets and membrane structures, or secreted into the circulation as VLDL particles. In the fasted state, the liver secretes glucose through both breakdown of glycogen (glycogenolysis) and de novo glucose synthesis (gluconeogenesis). During pronged fasting, hepatic gluconeogenesis is the primary source of endogenous glucose production. Fasting also promotes lipolysis in adipose tissue to release nonesterified fatty acids which are converted into ketone bodies in the liver though mitochondrial β oxidation and ketogenesis. Ketone bodies provide a metabolic fuel for extrahepatic tissues. Liver metabolic processes are tightly regulated by neuronal and hormonal systems. The sympathetic system stimulates, whereas the parasympathetic system suppresses, hepatic gluconeogenesis. Insulin stimulates glycolysis and lipogenesis, but suppresses gluconeogenesis; glucagon counteracts insulin action. Numerous transcription factors and coactivators, including CREB, FOXO1, ChREBP, SREBP, PGC-1α, and CRTC2, control the expression of the enzymes which catalyze the rate-limiting steps of liver metabolic processes, thus controlling liver energy metabolism. Aberrant energy metabolism in the liver promotes insulin resistance, diabetes, and nonalcoholic fatty liver diseases (NAFLD).

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Hepatic Deficiency in Transcriptional Cofactor TBL1 Promotes Liver Steatosis and Hypertriglyceridemia

Cited by 49 publications

References 45 publications

Amorfrutins are potent antidiabetic dietary natural products

Amorfrutins are potent antidiabetic dietary natural products

Control of diabetic hyperglycaemia and insulin resistance through TSC22D4

Energy Metabolism in the Liver

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