Hepatic Energy Metabolism under the Local Control of the Thyroid Hormone System

Abstract

The energy homeostasis of the organism is orchestrated by a complex interplay of energy substrate shuttling, breakdown, storage, and distribution. Many of these processes are interconnected via the liver. Thyroid hormones (TH) are well known to provide signals for the regulation of energy homeostasis through direct gene regulation via their nuclear receptors acting as transcription factors. In this comprehensive review, we summarize the effects of nutritional intervention like fasting and diets on the TH system. In parallel, we detail direct effects of TH in liver metabolic pathways with regards to glucose, lipid, and cholesterol metabolism. This overview on hepatic effects of TH provides the basis for understanding the complex regulatory network and its translational potential with regards to currently discussed treatment options of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) involving TH mimetics.

Keywords: NAFLD; T3; T4; cholesterol; deiodinase; energy metabolism; lipid metabolism.

Figure 1

Thyroid hormone signaling controls the reverse cholesterol transport from peripheral tissues to the liver (orange) as well as the cholesterol uptake, buildup (red), and turnover (green) in the liver on various rate-limiting stages. Besides the direct gene regulation, T3 signaling steers other transcription factors in the liver that mediate or amplify the T3 action (gray). A profile with a schematic protein icon is given for each known regulated gene, with (+) for T3-associated upregulation and (−) for T3-associated downregulation. The mechanism, if known, is depicted on that profile. Orchestration of transcription factors (gray) 11. T3 signaling not only regulates cholesterol metabolism in the liver via TR mediation but also positively influences SREBP2 expression via type 1 regulation and the activity of other involved transcription factors, such as PPARs and LXR, via type 3 regulation. Reverse cholesterol transport (orange) 1. Excess cholesterol from cells of the peripheral tissues is shuttled by cholesterol efflux regulatory protein (CERP). ABCA1 encodes this efflux pump and is regulated negatively by T3 but positively via nuclear receptors LXRs and PPARs. Cholesterol is transported from extrahepatic tissues via plasma back to the liver by binding to high-density lipoprotein (HDL) in blood vessels. 2. ApoAI forms the major component of HDL and is secreted by the liver. T3 upregulates Apoa1 transcription and increases mRNA stability. 3. HDL cholesterol can then either be taken up directly via SRB1, which has been increased in pharmacological studies with GC-1 and T-0681, or redistributed to other lipoprotein fractions. 4. The antiport mediated by the pore-forming CETP of cholesterol esters against triglycerides between HDL, on the one hand, and VLDL, intermediate density lipoprotein (ILD), and LDL, on the other hand, describes a pathway of indirect reverse cholesterol transport. 5. It is complemented by hepatic triglyceride lipase (encoded by LIPC) through the formation of the respective lipoprotein fractions. Both modulators are increased in serum in hyperthyroid patients, without known mechanisms. 6. LDL cholesterol can be endocytosed at the end of this cascade by a hepatic LDL receptor. Its gene is coregulated by T3 and SREPB2, whereas the regulation via T3 is the determinant independent of regulation via the sterol response element. 7. The serine protease PCSK9 circulating in serum can mediate its proteasomal termination upon binding to the LDL receptor and thus inhibit LDL uptake from serum. A negative regulation mainly via HNF1, but to a lesser extent also SREPB2, is described. Cholesterol biogenesis (red). The liver is the site of cholesterol biogenesis, which serves for 12 further downstream applications such as vitamin D or steroid hormone production or secretion via lipoproteins to stabilize global cellular membrane fluidity. 8. HMG-CoA reductase provides mevalonic acid as a rate-limiting step in cholesterol buildup; it is gene regulated by SREBP2 and undergoes mRNA stabilization by T3 signaling. Further cholesterol processing and secretion (green) 9. Excess cholesterol is converted to bile acid via CYP7A1, whose gene regulation is directly positively controlled by T3. 10. The ABCG5/G8 heterodimer complex mediates secretion of cholesterol and bile acids into the bile duct. Its activity is increased by T3 in the liver without any known mechanism.