Early induction of hepatic deiodinase type 1 inhibits hepatosteatosis during NAFLD progression - PubMed (original) (raw)

Early induction of hepatic deiodinase type 1 inhibits hepatosteatosis during NAFLD progression

Eveline Bruinstroop et al. Mol Metab. 2021 Nov.

Abstract

Objective: Nonalcoholic fatty liver disease (NAFLD) comprises a spectrum ranging from hepatosteatosis to progressive nonalcoholic steatohepatitis that can lead to cirrhosis. Humans with low levels of prohormone thyroxine (T4) have a higher incidence of NAFLD, and thyroid hormone treatment is very promising in all patients with NAFLD. Deiodinase type 1 (Dio1) is a hepatic enzyme that converts T4 to the bioactive T3 and therefore regulates thyroid hormone availability within hepatocytes. We investigated the role of this intrahepatic regulation during the progression of NAFLD.

Methods: We investigated hepatic thyroid hormone metabolism in two NAFLD models: wild-type mice fed a Western diet with fructose and Leprdb mice fed a methionine- and choline-deficient diet. AAV8-mediated liver-specific Dio1 knockdown was employed to investigate the role of Dio1 during the progression of NAFLD. Intrahepatic thyroid hormone levels, deiodinase activity, and metabolic parameters were measured.

Results: Dio1 expression and activity were increased in the early stages of NAFLD and were associated with an increased T3/T4 ratio. Prevention of this increase by AAV8-mediated liver-specific Dio1 knockdown increased hepatic triglycerides and cholesterol and decreased the pACC/ACC ratio and acylcarnitine levels, suggesting there was lower β-oxidation. Dio1 siRNA KD in hepatic cells treated with fatty acids showed increased lipid accumulation and decreased oxidative phosphorylation.

Conclusion: Hepatic Dio1 gene expression was modulated by dietary conditions, was increased during hepatosteatosis and early NASH, and regulated hepatic triglyceride content. These early adaptations likely represent compensatory mechanisms that reduce hepatosteatosis and prevent NASH progression.

Keywords: Deiodinase; Liver; NAFLD; NASH; Steatosis; Thyroid.

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Figures

Graphical abstract

Figure 1

Dio1 increases early during the progression of NAFLD (A) Western Diet with 15% fructose in the drinking water (WDF) for 8 and 16 weeks compared to Normal Chow Diet (NCD), (n = 7–8 per group) (B, C) Dio1 mRNA, Dio1 Activity in the WDF model, (D) Association between Deiodinase 1 activity and liver T3/T4 ratio in the WDF model (E) Mouse AML12 cell line with oleic acid and palmitic acid (OAPA) (6 wells per group) (F) Dio1 mRNA in the AML12 OAPA cell model (G–I) Liver triglycerides, Tnfa mRNA and Col1a1 mRNA in the WDF model (J) Leprdb model with normal chow diet (NCD) or methionine and choline deficient diet (MCD) compared to C57Bl6 with NCD diet (n = 6–10 per group) (K) Dio1 mRNA in the Leprdb model (K) Association between Deiodinase 1 activity and liver T3/T4 ratio in the Leprdb model (L–O) Liver triglycerides, Tnfa mRNA and Col1a1 mRNA in the Leprdb model. Data is depicted in mean ± SEM.

Figure 2

Dio1 KD increases liver triglycerides and cholesterol. (A) WDF model with injection of AAV8-Albumin-eGFP-mDio1-shRNAmir (WDF + Dio1 LKD) (n = 7) or AAV8-Albumin-eGFP-ctrl-shRNAmir (WDF + control) (n = 6). For reference, a group of NCD + control shRNA was included (n = 3). (B–G) Dio1 mRNA expression (B) DIO1 activity (C), liver triglycerides (TG; D), liver cholesterol (E), densitometric quantification of western blots analyzing pACC/ACC (F), C2/C4 acylcarnitines (G), C6 acylcarnitines (H) in the WDF Dio1 KD model. (I) Schematic representation of in vitro experiment utilizing mouse AML12 cell line treated with oleic acid and palmitic acid (OAPA) combined with Dio1 siRNA knockdown. (J) BODIPY staining of the AML12 cell line combined with OAPA and OAPA with Dio1 siRNA. (K) Change in oxygen consumption rate (OCR) after Dio1 siRNA in AML12 cells. (L–M) Tnfa mRNA (L), Col1a1 mRNA (M) in the WDF Dio1 KD model. (N) Histology of control NCD, control WDF, and Dio1 LKD WDF with TG content on average. Data is depicted in mean ± SEM.

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Early induction of hepatic deiodinase type 1 inhibits hepatosteatosis during NAFLD progression - PubMed (original) (raw)