Annexin A6 regulates adipocyte lipid storage and adiponectin release

Krautbauer, Sabrina; Haberl, Elisabeth M.; Eisinger, Kristina; Pohl, Rebekka; Rein-Fischboeck, Lisa; Rentero, Carles; Álvarez-Guaita, Anna; Enrich, Carlos; Grewal, Thomas; Buechler, Christa; Neumeier, Markus

doi:10.1016/j.mce.2016.09.033

Cited by 22 publications

(46 citation statements)

References 66 publications

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“…We recently identified reduced triglyceride accumulation in primary AnxA6-deficient hepatocytes upon oleate supply and lower lipid droplet numbers in liver sections from AnxA6-KO mice [ 42 ], indicating AnxA6 to participate in hepatic metabolism and liver physiology. In line with previous studies [ 28 , 47 ], plasma levels of the liver enzymes aspartate aminotransferase (67 ± 10.6 in WT vs. 90.5 ± 22.1 U/l in AnxA6-KO), alanine aminotransferase (25 ± 9.9 vs. 33.5 ± 5.1 U/l) and lactate dehydrogenase (858 ± 268.2 vs. 583 ± 164.1 U/l), as well as albumin (26.5 ± 1 vs. 23.5 ± 1.7 g/l) and total plasma protein (42.5 ± 4.9 vs. 46 ± 4.1 g/l) ( Fig 1A ) indicated normal liver function in AnxA6-KO animals fed a standard chow diet. Furthermore, body weight (29 ± 2 vs. 29 ± 9 g), total plasma cholesterol (82 ± 3 vs. 65 ± 8 mg/dl), triglycerides (70 ± 15 vs. 80 ± 5 mg/dl), free fatty acids (1.6 ± 0.3 vs. 1.5 ± 0.2 μmol/l), LDL (32 ± 2 vs. 24 ± 4 mg/dl), and HDL (38 ± 2 vs. 33 ± 3 mg/dl) in 8–12 weeks old control and AnxA6-KO animals were alike ( Fig 1A ).…”

Section: Resultssupporting

confidence: 94%

“…The data are presented relative to WT (100%). For absolute values, see text and [ 28 ] for further details. (B) H&E staining of liver sections from WT and AnxA6-KO mice on a chow diet.…”

Section: Resultsmentioning

confidence: 99%

“…AnxA6 is the largest member of the annexin family and may also contribute to control whole body lipid and glucose metabolism. In adipocytes, we and others showed that AnxA6 is associated with lipid droplets [ 26 – 28 ], and AnxA6 depletion reduced lipolysis [ 28 ]. Together with increased AnxA6 levels in white adipose tissue from obese mice, this suggested AnxA6 levels to influence fatty acid release from adipocytes [ 28 ], a critical risk factor for the development of fatty liver disease.…”

Section: Introductionmentioning

confidence: 99%

“…In adipocytes, we and others showed that AnxA6 is associated with lipid droplets [ 26 – 28 ], and AnxA6 depletion reduced lipolysis [ 28 ]. Together with increased AnxA6 levels in white adipose tissue from obese mice, this suggested AnxA6 levels to influence fatty acid release from adipocytes [ 28 ], a critical risk factor for the development of fatty liver disease. In hepatocytes, AnxA6 is highly abundant, making up approximately 0.25% of total liver protein [ 29 , 30 ].…”

Section: Introductionmentioning

confidence: 99%

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Altered hepatic glucose homeostasis in AnxA6-KO mice fed a high-fat diet

et al. 2018

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Annexin A6 (AnxA6) controls cholesterol and membrane transport in endo- and exocytosis, and modulates triglyceride accumulation and storage. In addition, AnxA6 acts as a scaffolding protein for negative regulators of growth factor receptors and their effector pathways in many different cell types. Here we investigated the role of AnxA6 in the regulation of whole body lipid metabolism and insulin-regulated glucose homeostasis. Therefore, wildtype (WT) and AnxA6-knockout (KO) mice were fed a high-fat diet (HFD) for 17 weeks. During the course of HFD feeding, AnxA6-KO mice gained less weight compared to controls, which correlated with reduced adiposity. Systemic triglyceride and cholesterol levels of HFD-fed control and AnxA6-KO mice were comparable, with slightly elevated high density lipoprotein (HDL) and reduced triglyceride-rich lipoprotein (TRL) levels in AnxA6-KO mice. AnxA6-KO mice displayed a trend towards improved insulin sensitivity in oral glucose and insulin tolerance tests (OGTT, ITT), which correlated with increased insulin-inducible phosphorylation of protein kinase B (Akt) and ribosomal protein S6 kinase (S6) in liver extracts. However, HFD-fed AnxA6-KO mice failed to downregulate hepatic gluconeogenesis, despite similar insulin levels and insulin signaling activity, as well as expression profiles of insulin-sensitive transcription factors to controls. In addition, increased glycogen storage in livers of HFD- and chow-fed AnxA6-KO animals was observed. Together with an inability to reduce glucose production upon insulin exposure in AnxA6-depleted HuH7 hepatocytes, this implicates AnxA6 contributing to the fine-tuning of hepatic glucose metabolism with potential consequences for the systemic control of glucose in health and disease.

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Section: Resultssupporting

confidence: 94%

“…The data are presented relative to WT (100%). For absolute values, see text and [ 28 ] for further details. (B) H&E staining of liver sections from WT and AnxA6-KO mice on a chow diet.…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Altered hepatic glucose homeostasis in AnxA6-KO mice fed a high-fat diet

et al. 2018

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“…Serum autoantibodies reactive to fetuin, showed utility as a prognostic indicator for PCa patients at risk of progressing to metastatic disease (34). In adipocytes, annexin (ANXA6) protein expression was up-regulated by high fat diet as well as oxidative stress (35). With respect to their relationship with cancer, low levels of ANXA6 expression were detected in localized PCa and were reduced during progression of the disease (36).…”

Section: CMmentioning

confidence: 99%

Human Periprostatic Adipose Tissue: Secretome from Patients With Prostate Cancer or Benign Prostate Hyperplasia

Sacca

Mazza

Scorticati

et al. 2018

Cancer Genomics Proteomics

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Background/Aim: Periprostatic adipose tissue (PPAT) directs tumour behaviour. Microenvironment secretome provides information related to its biology. This study was performed to identify secreted proteins by PPAT, from both prostate cancer and benign prostate hyperplasia (BPH) patients. Patients and Methods: Liquid chromatography-mass spectrometry-based proteomic analysis was performed in PPAT-conditioned media (CM) from patients with prostate cancer (CMs-T) (stage T3: CM-T3, stage T2: CM-T2) or benign disease (CM-BPH). Results: The highest number and diversity of proteins was identified in CM-T3. Locomotion was the biological process mainly associated to CMs-T and reproduction to CM-T3. Immune responses were enriched in CMs-T. Extracellular matrix and structural proteins were associated to CMs-T. CM-T3 was enriched in proteins with catalytic activity and CM-T2 in proteins with defense/immunity activity. Metabolism and energy pathways were enriched in CM-T3 and those with immune system functions in CMs-T. Transport proteins were enriched in CM-T2 and CM-BPH. Conclusion: Proteins and pathways reported in this study could be useful to distinguish stages of disease and may become targets for novel therapies.

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Annexin A6 Is Critical to Maintain Glucose Homeostasis and Survival During Liver Regeneration in Mice

et al. 2020

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BaCKgRoUND aND aIMS: Liver regeneration requires the organized and sequential activation of events that lead to restoration of hepatic mass. During this process, other vital liver functions need to be preserved, such as maintenance of blood glucose homeostasis, balancing the degradation of hepatic glycogen stores, and gluconeogenesis (GNG). Under metabolic stress, alanine is the main hepatic gluconeogenic substrate, and its availability is the rate-limiting step in this pathway. Na +-coupled neutral amino acid transporters (SNATs) 2 and 4 are believed to facilitate hepatic alanine uptake. In previous studies, we demonstrated that a member of the Ca 2+-dependent phospholipid binding annexins, Annexin A6 (AnxA6), regulates membrane trafficking along endo-and exocytic pathways. Yet, although AnxA6 is abundantly expressed in the liver, its function in hepatic physiology remains unknown. In this study, we investigated the potential contribution of AnxA6 in liver regeneration. appRoaCH aND ReSUltS: Utilizing AnxA6 knockout mice (AnxA6 −/−), we challenged liver function after partial hepatectomy (PHx), inducing acute proliferative and metabolic stress. Biochemical and immunofluorescent approaches were used to dissect AnxA6 −/− mice liver proliferation and energetic metabolism. Most strikingly, AnxA6 −/− mice exhibited low survival after PHx. This was associated with an irreversible and progressive drop of blood glucose levels. Whereas exogenous glucose administration or restoration of hepatic AnxA6 expression rescued AnxA6 −/− mice survival after PHx, the sustained hypoglycemia in partially hepatectomized AnxA6 −/− mice was the consequence of an impaired alanine-dependent GNG in AnxA6 −/− hepatocytes. Mechanistically, cytoplasmic SNAT4 failed to recycle to the sinusoidal plasma membrane of AnxA6 −/− hepatocytes 48 hours after PHx, impairing alanine uptake and, consequently, glucose production.

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Annexin A6 regulates adipocyte lipid storage and adiponectin release

Cited by 22 publications

References 66 publications

Altered hepatic glucose homeostasis in AnxA6-KO mice fed a high-fat diet

Altered hepatic glucose homeostasis in AnxA6-KO mice fed a high-fat diet

Human Periprostatic Adipose Tissue: Secretome from Patients With Prostate Cancer or Benign Prostate Hyperplasia

Annexin A6 Is Critical to Maintain Glucose Homeostasis and Survival During Liver Regeneration in Mice

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