FoxO transcription factors are required for hepatic HDL cholesterol clearance

Lee, Samuel X.; Heine, Markus; Schlein, Christian; Ramakrishnan, Rajasekhar; Liu, Jing; Belnavis, Gabriella; Haimi, Ido; Fischer, Alexander W.; Ginsberg, Henry N.; Heeren, Joerg; Rinninger, Franz; Haeusler, Rebecca A.

doi:10.1172/jci94230

Cited by 19 publications

(21 citation statements)

References 89 publications

(91 reference statements)

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“…Nuclear exclusion of the transcription factor FoxO1 has been proposed to mediate the suppressive effects of insulin on Apoc3 expression (31). To determine whether Apoc3 is regulated by FoxO transcription factors, we measured Apoc3 mRNA expression in mice with liver-targeted deletions of FoxO1, FoxO3, and FoxO4 (Supplemental Figure 1A), using a previously described model (32). Contrary to experiments based on forced overexpression of FoxO1 (31), we found that hepatocyte deletion of FoxOs did not alter Apoc3 mRNA levels in mice fasted for 4 hours during the dark cycle (Supplemental Figure 1B).…”

Section: Resultsmentioning

confidence: 99%

Increased apolipoprotein C3 drives cardiovascular risk in type 1 diabetes

Kanter¹,

Shao²,

Kramer³

et al. 2019

Journal of Clinical Investigation

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142

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Type 1 diabetes mellitus (T1DM) increases the risk of atherosclerotic cardiovascular disease (CVD) in humans by poorly understood mechanisms. Using mouse models of T1DM-accelerated atherosclerosis, we found that relative insulin deficiency, rather than hyperglycemia, elevated levels of apolipoprotein C3 (APOC3), an apolipoprotein that prevents clearance of triglyceride-rich lipoproteins (TRLs) and their remnants. We then showed that serum APOC3 levels predict incident CVD events in subjects with T1DM in the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study. To explore underlying mechanisms, we examined the impact of Apoc3 antisense oligonucleotides (ASOs) on lipoprotein metabolism and atherosclerosis in a mouse model of T1DM. Apoc3 ASO treatment abolished the increased hepatic expression of Apoc3 in diabetic mice, resulting in lower levels of TRLs, without improving glycemic control. APOC3 suppression also prevented arterial accumulation of APOC3-containing lipoprotein particles, macrophage foam cell formation, and accelerated atherosclerosis in diabetic mice. Our observations demonstrate that relative insulin deficiency increases APOC3 and that this results in elevated levels of TRLs and accelerated atherosclerosis in a mouse model of T1DM. Because serum levels of APOC3 predicted incident CVD events in the CACTI study, inhibition of APOC3 might reduce CVD risk in patients with T1DM.

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Section: Resultsmentioning

confidence: 99%

Increased apolipoprotein C3 drives cardiovascular risk in type 1 diabetes

Kanter¹,

Shao²,

Kramer³

et al. 2019

Journal of Clinical Investigation

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142

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“…We transduced adult FoxO1 F/F , FoxO3 F/F , and FoxO4 F/Y control mice with an adenoassociated virus expressing Cre recombinase under the hepatocyte-specific Tbg promoter (AAV8.Tbg.Cre). We verified that one month after the injection, there was a >80% depletion of FoxO mRNA expression as well as low levels of G6pc, a known target of FoxO transcriptional activation 14 . In these FoxO-depleted mice, we found that the Apom mRNA expression is significantly decreased (Fig.…”

Section: Foxos Are Required For Hepatic Apom Expressionmentioning

confidence: 52%

“…Moreover, our data indicate that the majority of plasma ApoM arises from hepatic secretion, and that hepatic ApoM is required only for HDL-associated S1P, not total plasma S1P. We recently demostrated that hepatic FoxOs also promote clearance of HDL-cholesterol, by promoting expression of Scarb1, encoding scavenger receptor BI (SR-BI), and Lipc, encoding hepatic lipase 14 . Together with the novel data in this manuscript, these findings suggest that there are at least two independent mechanisms by which hepatic FoxOs regulate HDL composition.…”

Section: Discussionmentioning

confidence: 89%

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Hepatic FoxOs induce apolipoprotein M and are required for sphingosine-1-phosphate to bind high density lipoproteins

Izquierdo

Shanmugarajah

Lee

et al. 2019

Preprint

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The authors declare no conflicts of interest.Abbreviations: AAV=adeno-associated virus, ApoM=apolipoprotein M, DIO=diet induced obese, FPLC=fast protein liquid chromatography, HDL=high density lipoprotein, HFD=high fat diet, LC-MS/MS=liquid chromatography-mass spectrometry, LDL=low density lipoprotein, LPD=lipoprotein depleted, S1P=sphingosine-1-phosphate, Tbg=thyroxin binding globulin, VLDL=very low density lipoprotein, WTD=western type diet ABSTRACTThe FoxO family of transcription factors play an important role in mediating insulin action on glucose, lipid, and lipoprotein metabolism. Liver-specific triple FoxO knockout mice (L-FoxO1,3,4) have defects in expression of genes related to glucose production, bile acid synthesis, and high density lipoprotein (HDL)-cholesterol uptake. We have now identified Apolipoprotein M (Apom) as a novel transcriptional target of liver FoxO. ApoM is a liver-secreted apolipoprotein that is bound to HDL in the circulation, and it serves as a chaperone for the bioactive lipid, sphingosine-1-phosphate (S1P). Several recent studies have demonstrated that S1P bound to ApoM induces unique effects, compared to S1P bound to albumin. We now show that liver FoxOs are required for ApoM mRNA and protein expression, and that ApoM is a transcriptional target of FoxOs. Moreover, while total plasma S1P levels are similar between control and L-FoxO1,3,4 mice, S1P is nearly absent from HDL in L-FoxO1,3,4 mice, and is instead increased in the lipoprotein depleted fraction. We also observed that leptin receptor deficient db/db mice have low hepatic Apom mRNA, and low levels of ApoM and S1P in HDL, without changes in total plasma S1P. These data demonstrate that FoxO transcription factors are novel regulators of the ApoM-S1P pathway, and indicate a potential link between hepatic insulin action and HDL function. METHODS Mice and diets.All experiments were approved by the Columbia University Institutional Animal Care and Use Committee. L-FoxO1,3,4 mice have been previously described 5,9 . Males at least 12 weeks old were studied, except in studies of 2-day-old pups, which were of mixed sex. For the acute FoxO depletion experiments, adult Foxo1 fl/fl , Foxo3 fl/fl , and Foxo4 fl/Y control mice were transduced with adeno-associated virus (serotype 8) expressing Cre recombinase driven by the hepatocyte-specific Tbg promoter (AAV8.Tbg. Cre) or control virus (AAV.GFP). Mice were injected intravenously with 1×10 11 virus particles/mouse, 4 weeks prior to euthanasia. AAV8.Tbg.Cre was a gift ). For the adenovirus experiments, adult male mice were injected intravenously with murine ApoM adenovirus (Welgen) 0.5 × 10 9 virus particles/gram of body weight, 8 days prior to euthanasia. For the db/db studies, male db/db and db/+ mice were purchased from Jackson Laboratory and were studied when they were 12, 13 or 25 weeks old. For the diet induced obesity studies, male C57BL/6J mice were purchased from Jackson Laboratory when they were 6 weeks old. Mice were fed either a standard chow diet (Purina) or a high fat diet ...

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“…They have higher levels of triglycerides and it is known that the triglycerides themselves encourage gallstone formation. (13) Another theory is that stones form because of what is called autonomic neuropathy or damage from diabetes to the involuntary nerves that control movement of the bowels and gallbladder. According to this line of thought the bile stored in the gallbladder is not released efficiently, because the nerves are damaged and gallstones form from the resulting sludge.…”

Section: Resultsmentioning

confidence: 99%

Epidemiological and Pathological Studies of Gallstone Disease in Patients of Lucknow Region

Misra¹,

Sharma²,

Chaubey³

et al. 2018

jemds

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BACKGROUND Gallstone disease is the most common gastrointestinal problem associated with gallbladder affecting millions of people throughout the world. The gallstones are solid crystalline precipitates in the biliary tract, usually formed in the gallbladder. Cholesterol and calcium bilirubinate are the two main substances involved in gallstone formation. Based on their chemical composition, gallstones are classified as cholesterol, pigment and mixed stones. (1) The colour of gallstones may be white, yellow, brown, black and green. Cholesterol stones are usually yellow, but are sometimes white in colour. Mixed stones are usually smaller, multiple in numbers and occur in various colours and shapes. Pigment gallstone may be brown or black, which mainly consists of bilirubin and calcium salts such as calcium carbonate. (2) The incidence of this disease shows substantial geographical variation with higher incidence in North Indian people as compared to South Indian people. (3) Dietary habits and lifestyle of the patient are going to influence the formation of gallstone. (4) High biliary protein and lipid concentration are risk factors for the formation of gallstones, while gallbladder sludge is thought to be usual precursor of gallstone formation. Age, gender and ethnicity are the most important factors predisposing its prevalence in population. (5) Gallstone disease is related to several cardiometabolic risk factors such as obesity, dyslipidaemias (Hypertriglyceridaemia and low-high-density lipoprotein and high cholesterol), diabetes, unhealthy diet and sedentary lifestyle. High-risk factor for the cholesterol dominant gallstones is the obese individuals with a body mass index of 30 kg/sq. metre. (6) People with diabetes are at higher risk for gallstone disease and gallbladder disease may progress more rapidly in patients with diabetes who are obese and tend to have infection. (7) This study was aimed to confirm the prevalence of various types of gallstones in rural population of Lucknow region with concern to most common age group and sex including common clinical features manifested during the course of the disease. MATERIALS AND METHODS This study is a retrospective descriptive study, which included 132 patients over a period of 18 months (from July 2015 to December 2016) with diagnosis based on abdominal ultrasound report and further confirmed by biochemical test. Detailed history of all patients was taken with reference to dietary habits, age, sex and metabolic diseases (Diabetes) and lab reports from MR department. These cases were systematised to find out the cumulative prevalence rate of gallstone disease among rural population of Lucknow region, because TSM Hospital caters services mostly to rural patient. Previous records of abdominal ultrasound were reviewed, which were available in MR department of hospital during July 2015 to December 2016. Data was tabulated separately and cases for positive and negative for gallstones disease were identified and gallstones of patients available in pathology department ...

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FoxO transcription factors are required for hepatic HDL cholesterol clearance

Cited by 19 publications

References 89 publications

Increased apolipoprotein C3 drives cardiovascular risk in type 1 diabetes

Increased apolipoprotein C3 drives cardiovascular risk in type 1 diabetes

Hepatic FoxOs induce apolipoprotein M and are required for sphingosine-1-phosphate to bind high density lipoproteins

Epidemiological and Pathological Studies of Gallstone Disease in Patients of Lucknow Region

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