Hepatocyte sortilin 1 knockout and treatment with a sortilin 1 inhibitor reduced plasma cholesterol in Western diet-fed mice

Chen, Cheng; Li, Jibiao; Matye, David J.; Wang, Yifeng; Li, Tiangang

doi:10.1194/jlr.m089789

Cited by 32 publications

(38 citation statements)

References 40 publications

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“…Our analyses identified a number of variants previously implicated in lipid and glucose metabolism. Sortilin 1 (SORT1) is highly expressed in adipocytes, and the sortilin gene product facilitates the formation and export of VLDL from the liver (49,50). The role of SORT1 in T2D risk is not well understood.…”

Section: Discussionmentioning

confidence: 99%

Phenotypic and Genetic Characterization of Lower LDL Cholesterol and Increased Type 2 Diabetes Risk in the UK Biobank

et al. 2020

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Although hyperlipidemia is traditionally considered a risk factor for type 2 diabetes (T2D), evidence has emerged from statin trials and candidate gene investigations suggesting that lower LDL cholesterol (LDL-C) increases T2D risk. We thus sought to more comprehensively examine the phenotypic and genotypic relationships of LDL-C with T2D. Using data from the UK Biobank, we found that levels of circulating LDL-C were negatively associated with T2D prevalence (odds ratio 0.41 [95% CI 0.39, 0.43] per mmol/L unit of LDL-C), despite positive associations of circulating LDL-C with HbA 1c and BMI. We then performed the first genome-wide exploration of variants simultaneously associated with lower circulating LDL-C and increased T2D risk, using data on LDL-C from the UK Biobank (n 5 431,167) and the Global Lipids Genetics Consortium (n 5 188,577), and data on T2D from the Diabetes Genetics Replication and Meta-Analysis consortium (n 5 898,130). We identified 31 loci associated with lower circulating LDL-C and increased T2D, capturing several potential mechanisms. Seven of these loci have previously been identified for this dual phenotype, and nine have previously been implicated in nonalcoholic fatty liver disease. These findings extend our current understanding of the higher T2D risk among individuals with low circulating LDL-C and of the underlying mechanisms, including those responsible for the diabetogenic effect of LDL-C-lowering medications.

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Section: Discussionmentioning

confidence: 99%

Phenotypic and Genetic Characterization of Lower LDL Cholesterol and Increased Type 2 Diabetes Risk in the UK Biobank

et al. 2020

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“…Our analyses identified a number of variants previously implicated in lipid and glucose metabolism. Sortilin 1 ( SORT1 ) is highly expressed in adipocytes, and the sortilin gene product facilitates the formation and export of VLDL from the liver (44,45). The role of SORT1 in T2D risk is not well understood.…”

Section: Discussionmentioning

confidence: 99%

Type-2 diabetes with low LDL-C: genetic insights into a unique phenotype

Klimentidis

Arora

Newell

et al. 2019

Preprint

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21Although hyperlipidemia is traditionally considered a risk factor for type-2 diabetes (T2D), 22 evidence has emerged from statin trials and candidate gene investigations suggesting that lower 23 LDL-C increases T2D risk. We thus sought to comprehensively examine the phenotypic and 24 genotypic relationships of LDL-C with T2D. Using data from the UK Biobank, we found that 25 LDL-C was negatively associated with T2D (OR=0.43[0.41, 0.45] per mmol/L unit of LDL-C), 26 despite positive associations of LDL-C with HbA1c and BMI. We then performed the first 27 genome-wide exploration of variants simultaneously associated with lower LDL-C and increased 28 T2D risk, using data on LDL-C from the UK Biobank (n=431,167) and the GLGC consortium 29 (n=188,577), and T2D from the DIAGRAM consortium (n=898,130). We identified 31 loci 30 associated with lower LDL-C and increased T2D, capturing several potential mechanisms. Seven 31 of these loci have previously been identified for this phenotype, and 9 have previously been 32 implicated in non-alcoholic fatty liver disease. Finally, two-sample Mendelian randomization 33 analyses suggest that low LDL-C causes T2D, although causal interpretations are challenging 34 due to pleiotropy. Our findings extend our current understanding of the higher T2D risk among 35 individuals with low LDL-C, and of the underlying mechanisms, including those underlying the 36 diabetogenic effect of LDL-C-lowering medications. 38Rates of cardiovascular disease (CVD) and type-2 diabetes (T2D) are among the most 39 pressing health concerns worldwide. These two diseases share many risk factors, and tend to co-40 occur; T2D carries a 2-4 fold increase in risk for CVD, and more than 70% of patients with T2D 41 will die from cardiovascular complications (1). Yet, there remains controversy over whether all 42 risk factors exert similar effects on the risk of these two conditions. Low-density lipoprotein 43 cholesterol (LDL-C) is a class of highly atherogenic particles, and circulating levels of LDL-C 44 are a causal risk factor for CVD across the lifespan (2). Lipid lowering medications, in particular 45 from the statin drug class, are effective at lowering levels of LDL-C which has a dose-response 46 relationship with a reduction in adverse cardiovascular events (3). The perception of a strong 47 inter-relationship of T2D with hyperlipidemia, in particular higher LDL-C, has led to a standard 48 of care in which lipid-lowering medications are a common therapeutic option for T2D. For 49 example, the American Diabetes Association (ADA) recommends high intensity statin use for 50 individuals with diabetes with prevalent atherosclerotic cardiovascular disease (ASCVD) or a 51 greater than 20% 10-year risk of ASCVD until they reach recommended stringent targets of 52 LDL-C < 70mg/dL. The ADA further recommends moderate-intensity statin use for T2D 53 patients 40 years and older without ASCVD (4). 54A recent analysis of national registry data from Scotland showed that 83.6% and 71.1% 55 of T2D patients with and...

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“…One week post injection, mice were challenged with WD for 1 week. Mice were fasted for 6 h and VLDL secretion assay was performed as previously described 62 . Briefly, mice were i.v.…”

Section: Methodsmentioning

confidence: 99%

An FGF15/19-TFEB regulatory loop controls hepatic cholesterol and bile acid homeostasis

Wang

Gunewardena

et al. 2020

Nat Commun

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Bile acid synthesis plays a key role in regulating whole body cholesterol homeostasis. Transcriptional factor EB (TFEB) is a nutrient and stress-sensing transcriptional factor that promotes lysosomal biogenesis. Here we report a role of TFEB in regulating hepatic bile acid synthesis. We show that TFEB induces cholesterol 7α-hydroxylase (CYP7A1) in human hepatocytes and mouse livers and prevents hepatic cholesterol accumulation and hypercholesterolemia in Western diet-fed mice. Furthermore, we find that cholesterol-induced lysosomal stress feed-forward activates TFEB via promoting TFEB nuclear translocation, while bile acid-induced fibroblast growth factor 19 (FGF19), acting via mTOR/ERK signaling and TFEB phosphorylation, feedback inhibits TFEB nuclear translocation in hepatocytes. Consistently, blocking intestinal bile acid uptake by an apical sodium-bile acid transporter (ASBT) inhibitor decreases ileal FGF15, enhances hepatic TFEB nuclear localization and improves cholesterol homeostasis in Western diet-fed mice. This study has identified a TFEB-mediated gut-liver signaling axis that regulates hepatic cholesterol and bile acid homeostasis.

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Hepatocyte sortilin 1 knockout and treatment with a sortilin 1 inhibitor reduced plasma cholesterol in Western diet-fed mice

Cited by 32 publications

References 40 publications

Phenotypic and Genetic Characterization of Lower LDL Cholesterol and Increased Type 2 Diabetes Risk in the UK Biobank

Phenotypic and Genetic Characterization of Lower LDL Cholesterol and Increased Type 2 Diabetes Risk in the UK Biobank

Type-2 diabetes with low LDL-C: genetic insights into a unique phenotype

An FGF15/19-TFEB regulatory loop controls hepatic cholesterol and bile acid homeostasis

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