Insight into Potential Interactions of Thyroid Hormones, Sex Hormones and Their Stimulating Hormones in the Development of Non-Alcoholic Fatty Liver Disease

Abstract

Non-Alcoholic Fatty Liver Disease (NAFLD) is a common manifestation of metabolic syndrome. In addition to lifestyle, endocrine hormones play a role in the dysregulation of hepatic metabolism. The most common endocrine hormones contributing to metabolic syndrome are alterations in the levels of thyroid hormones (THs, predominantly in subclinical hypothyroidism) and of sex hormones (in menopause). These hormonal changes influence hepatic lipid and glucose metabolism and may increase hepatic fat accumulation. This review compares the effects of sex hormones, THs and the respective stimulating hormones, Thyroid-Stimulating Hormone (TSH) and Follicle-Stimulating Hormone (FSH), on the development of hepatosteatosis. TSH and FSH may be more relevant to the dysregulation of hepatic metabolism than the peripheral hormones because metabolic changes were identified when only levels of the stimulating hormones were abnormal and the peripheral hormones were still in the reference range. Increased TSH and FSH levels appear to have additive effects on the development of NAFLD and to act independently from each other.

Keywords: follicle-stimulating hormone; hypothyroidism; menopause; metabolic dysfunction-associated fatty liver disease; metabolic syndrome; thyroid-stimulating hormone.

Figure 1

Enzymes relevant for the homeostasis of glucose, lipid and cholesterol homeostasis in healthy hepatocytes. Phosphoenolpyruvate Carboxykinase (PEPCK) converts phosphoenolpyruvate into oxaloacetate and is the rate-limiting step in gluconeogenesis. Pyruvate Kinase (PK) is the last step in glycolysis and transfers a phosphate group from phosphoenolpyruvate to pyruvate. Glucose may also be generated by Glucose-6-Phosphatase (G6Pase). The main role in glycogenesis is exerted by Glycogen Synthase (GS). Tricarboxylic Acid cycle (TCA) and β-oxidation of Fatty Acids (FAs) in the mitochondria serve for energy production. Activity of Carnitine Palmitoyl Transferase 1 (CPT1) determines the extent of β-oxidation. Lipogenesis is regulated through action of Acetyl-CoA Carboxylase 1 (ACC), Fatty Acid Synthase (FAS), Stearoyl-CoA Desaturase (SCD1) and Elongation of Very-Long chain fatty acids protein 6 (ELOVL6). Diacylglycerol O-Acyltransferase 2 (DGAT2) catalyzes the formation of Triglycerides (TGs) from diacylglycerol and fatty acid-CoA. Microsomal Triglyceride Transfer Protein (MTTP) is essential for the assembly with apoB100 in the synthesis of Very-Low-Density Lipoprotein (VLDL). Cholesterol may be synthesized de novo from Acetyl-CoA by β-Hydroxy-β-Methylglutaryl Coenzyme A Reductase (HMGCR) as rate-limiting step in the synthesis. Acyl-CoA Cholesterol Acyltransferase (ACAT) produces Cholesterol Esters (CE) that are integrated into VLDL by Cholesteryl Ester Transfer Protein (CETP). Cholesterol can also be metabolized to bile acids by the action of Cholesterol 7a-hydrolase (CYP7A1). Cholesterol may be taken up as Low-Density Lipoprotein (LDL) cholesterol by LDL Receptor (LDLR), as HDL cholesterol by scavenger receptor class B type 1 (SRB1) and as Chylomicron remnants (Chylo-remn.) by LDLR in humans and LDLR-related Protein 1 (LRP1) in rodents. Surface proteins are Apolipoprotein (Apo)B48 for chylomicron remnants, ApoB100 for VLDL and LDL, and ApoA1 for HDL cholesterol particles. Free Fatty Acids (FFAs) can be taken up by CD36, also termed Fatty Acid Translocase (FAT). Abbreviation: M, mitochondrion.

Figure 2

Changes in hepatic metabolism in insulin resistance and Non-Alcoholic Fatty Liver Disease (NAFLD). Glucose is metabolized to acetyl-CoA and used for synthesis of fatty acids and cholesterol. Free Fatty Acids (FFAs) are taken up by the CD36 receptor. The increased intracellular FA levels activate α-oxidation in the mitochondria. Due to the defective function of the respiratory chain in NAFLD, generation of reactive oxygen species is increased and induces inflammation. Excess Triglycerides (TGs) may accumulate in the hepatocytes or be exported into the blood. The export of TGs and cholesterol, however, is decreased in NAFLD due to impaired VLDL synthesis. Gluconeogenesis and hepatic output of glucose continues similar to the fasted condition. Abbreviations: Apo, apolipoprotein; Chylo-remn., Chylomicron Remnants; HDL, High-Density Lipoprotein; LDLR, LDL Receptor; LRP1, LDLR-Related Protein 1; M, Mitochondrion; SRB1, Scavenger Receptor Class B Type 1; VLDL, Very-Low-Density Lipoprotein.

Figure 3

Influence of TH on lipid and cholesterol metabolism. (a): T3 stimulates lipogenesis by increase of Fatty Acid Translocase (FAT), Fatty Acid Binding Protein (FABP), upregulation of Fatty Acid Synthase (FAS), Acetyl-CoA Carboxylase (ACC), Malic Enzyme (ME), Spot 14 homolog (Spot14), decrease of Sterol Regulatory Element-Binding Protein 1c (SREBP-1c) and Peroxisome Proliferator Activated Receptor (PPAR)-γ combined with increase of Carbohydrate-Responsive Element-Binding Protein (ChREBP) and Liver X Receptor (LXR) and decrease of Stearoyl-CoA Desaturase (SCD1) and Glycerol-3-Phosphate Acyltransferase (GPAT). TSH acts on lipogenesis through upregulation of c-AMP, Protein Kinase A (PKA) and PPAR-α, which cause activation of SREBP-1c. T3 stimulates lipolysis by upregulation of Hepatic Lipase (HL) and Adipose Triglyceride Lipase (ATGL). β-Oxidation is activated by increased expression of CPT1 and the mitochondrial enzymes, Medium-Chain Acyl-CoA Dehydrogenase (MCAD), Pyruvate Dehydrogenase Kinase isoform 4 (PDK4) and mitochondrial Uncoupling Protein 2 (UCP2). The CPT1 expression can also be stimulated via PPAR-α, Sirtuin 1 (SIRT1), Fibroblast Growth Factor 21 (FGF21), Estrogen-Related Receptor α (ERRα) and PPARγ-Coactivator 1α (PGC-1α), to increase uptake of Fatty Acids (FAs) in the mitochondria. Further, synthesis of mitochondria, mitophagy, lipophagy, degradation of lipids in lysosomes and enzyme activity of peroxisomes are induced by T3. Abbreviations: L, lysosome; Lp, lipophagy; M, mitochondrion; Mp, mitophagy; P, peroxisome. (b): Cholesterol synthesis is affected by T3 at the level of synthesis by induction of β-Hydroxy-β-Methylglutaryl-CoA Reductase (HMGCR) and Farnesyl Pyrophosphate Synthase (FPPS), secretion by downregulation of Sterol O-Acyltransferase 2 (SOAT2) and Apolipoprotein 100 (ApoB100), clearance by upregulation of Cholesteryl Ester Transfer Protein (CETP) and Low-Density Lipoprotein Receptor (LDLR), excretion by upregulation of CYP7A1 and uptake of HDL cholesterol by Scavenger Receptor Class B (SRB1) and of LDL cholesterol by LDLR and Low-Density Lipoprotein Receptor-related Protein (LRP1). Cholesterol levels are increased by TSH through upregulation of HMGCR and SREBP-2. Increased levels are indicated by red and decreases by blue color. Regulated genes are written in italics.

Figure 4

Changes in lipogenesis, lipolysis and cholesterol under the influence of estrogens and Follicle-Stimulating Hormone (FSH). Levels of Sterol Regulatory Element-binding Protein (SREBP-1c) and enzymes of Fatty Acid (FA) synthesis, Fatty Acid Synthase (FAS), Acetyl-CoA Carboxylase (ACC), Stearoyl-CoA Desaturase (SCD1) and Glycerol-3-Phosphate Acyltransferase (GPAT) are decreased. Estrogens increase lipolysis by stimulation of Acyl-CoA Dehydrogenase (ACD), 3-Ketoacyl-CoA Thiolase (KAT) and Carnitine Palmitoyl Transferase 1 (CPT1). Further, Peroxisome Proliferator-Activated Receptor (PPAR)-α and Fibroblast Growth Factor (FGF)21 levels and Mitophagy (Mp) are increased. Estrogens decrease cholesterol synthesis by downregulation of β-Hydroxy-β-Methylglutaryl Coenzyme A Reductase (HMGCR). Upregulation of Cholesterol 7a-hydrolase (CYP7A1) increases transformation of cholesterol into bile acids. Uptake of cholesterol is increased by upregulation of Scavenger Receptor Class B (SRB1) and Low-Density Lipoprotein Receptor (LDLR) or Low-Density Lipoprotein Receptor-related Protein (LRP1). FSH increases cholesterol synthesis by upregulation of HMGCR and decreases uptake by downregulation of LDLR or LRP1. Increased levels are indicated by red and decreases by blue color. Regulated genes are written in italic.