Hepatic transforming growth factor-β 1 stimulated clone-22 D1 controls systemic cholesterol metabolism

Abstract

Disturbances in lipid homeostasis are hallmarks of severe metabolic disorders and their long-term complications, including obesity, diabetes, and atherosclerosis. Whereas elevation of triglyceride (TG)-rich very-low-density lipoproteins (VLDL) has been identified as a risk factor for cardiovascular complications, high-density lipoprotein (HDL)-associated cholesterol confers atheroprotection under obese and/or diabetic conditions. Here we show that hepatocyte-specific deficiency of transcription factor transforming growth factor β 1-stimulated clone (TSC) 22 D1 led to a substantial reduction in HDL levels in both wild-type and obese mice, mediated through the transcriptional down-regulation of the HDL formation pathway in liver. Indeed, overexpression of TSC22D1 promoted high levels of HDL cholesterol in healthy animals, and hepatic expression of TSC22D1 was found to be aberrantly regulated in disease models of opposing energy availability. The hepatic TSC22D1 transcription factor complex may thus represent an attractive target in HDL raising strategies in obesity/diabetes-related dyslipidemia and atheroprotection.

The gut microbiota instructs the hepatic endothelial cell transcriptome

“…In contrast to a previous study showing the regulation of the Na + -dependent bile acid transporter solute carrier family 10 member 6 ( Slc10a6 ) via lipopolysaccharide signaling, depending on the nuclear receptor farnesoid X receptor (FXR) and the retinoid X receptor ( Kosters et al., 2016 ; Sawkat Anwer and Stieger, 2014 ), we found increased expression of Slc10a6 at GF housing conditions. In line with increased plasma lipoprotein levels at chow diet at GF housing conditions ( Kiouptsi et al., 2019 ), expression of Tsc22d1 , encoding a transcription factor that is critically involved in the formation of high-density lipoprotein (HDL) particles ( Jäger et al., 2014 ), was increased in the hepatic endothelium of GF mice. Moreover, lipase A , coding for the enzyme hydrolyzing cholesteryl esters and triglycerides in the lysosome, that is a known regulator of the mTOR pathway and the endothelial barrier ( Zhao et al., 2014 , 2017 ), was upregulated at GF housing conditions.…”

Regulation of protein-coding gene and long noncoding RNA pairs in liver of conventional and germ-free mice following oral PBDE exposure

“…Pattern 2 included 5 genes ( Fig 2C ), which were down-regulated by both PBDEs in CV and GF mice, including family with sequence similarity genes (Fam222a); Fam89a; nuclear factor interleukin 3 (Nfil3), which plays a critical role in the regulation of apoptosis in lymphocytes [ 84 ]; Ppard, which suppresses hepatic lipogenesis in obese mice [ 85 ]; and transforming growth factor beta-stimulated clone 22 homolog (Tsc22d1), which controls systemic cholesterol metabolism. Overexpression of Tsc22d1 promotes high levels of high-density lipoprotein (HDL) cholesterol in mice [ 86 ]. Pattern 3 included 9 genes ( Fig 2D ), which were consistently down-regulated by BDE-47 in CV and GF mice, but were down-regulated by BDE-99 in CV mice and up-regulated by BDE-99 in GF mice.…”

“…NONMMUG004004.2 and Gstt3 were also up-regulated by BDE-47 in livers of GF mice ( Fig 5B ). In addition, several lncRNA-paired PCGs involved in cholesterol and lipid metabolism were down-regulated by BDE-47 in livers of GF mice: NONMMUG029453.1, which is transcribed from the downstream region of Gm2083; NONMMUG013481.2, which is transcribed from the intronic region of Tsc22d1 that is related to cholesterol metabolism [ 86 ]; as well as NONMMUG020688.1, which is transcribed from the intronic region of transmembrane 7 superfamily member 2 (Tm7sf2, also known as delta(14)-sterol reductase) that is responsible for sterol biosynthesis [ 140 ].…”

TSC-22 up-regulates collagen 3a1 gene expression in the rat heart

“…TGF-β activates transcription factors such as SMAD proteins, and TSC-22. TSC-22 is suggested to have functions in controlling tumorigenesis, apoptosis, cholesterol homeostasis, cardiac fibrosis as well as development and differentiation processes [ 14 – 23 ]. Overall in this study, we extended knowledge of the role of TSC-22 in the heart.…”

“…Although the DNA binding surface of TSC-22 differs from that of the other basic leucine zipper proteins, it can homodimerize and heterodimerize with other transcription factors such as SMADs [ 11 – 14 ], and it has transcriptional repression activity [ 11 ]. Several physiological roles for TSC-22 have been identified: TSC-22 is thought to be a tumour suppressor in several cancer cell lines and tumour tissue [ 15 – 21 ], regulating developmental processes in Xenopus laevis during gastrulation and in oogenesis of Drosophila melanogaster [ 14 , 22 ], apoptosis [ 17 , 21 ], and systemic cholesterol metabolism [ 23 ] as well as promoting cardiac myofibroblast differentiation and fibrosis [ 13 ]. TSC-22 is up-regulated by many stimuli, including different cytokines, fibroblast growth factor 2 (FGF2), and epidermal growth factor (EGF) [ 24 ].…”