Hepatic Deficiency of Augmenter of Liver Regeneration Predisposes to Nonalcoholic Steatohepatitis and Fibrosis.
Hepatology
; 72(5): 1586-1604, 2020 11.
Article
en En
| MEDLINE
| ID: mdl-32031683
ABSTRACT
BACKGROUND AND AIMS:
The augmenter of liver regeneration (ALR) protein is critical for lipid homeostasis and mitochondrial function. We investigated high-fat/high-carbohydrate (HF/HC) diet-induced nonalcoholic fatty liver disease (NAFLD) in wild-type (WT), hepatocyte-specific ALR-knockout (ALR-H-KO), and ALR-heterozygous (ALR-H-HET) mice. ALR was measured in serum of human nonalcoholic steatohepatitis (NASH) and NASH-induced cirrhosis (serum and liver). APPROACH ANDRESULTS:
HF/HC feeding decreased ALR expression in all groups of mice. The otherwise normal ALR-H-HET mice gained more weight and steatosis than WT mice when challenged metabolically with the HF/HC diet; ALR-H-KO mice gained the least weight and had the least steatosis. These findings were consistent with correspondingly increased triglycerides and cholesterol and altered expression of carnitine palmitoyltransferase 1a, sterol regulatory element-binding protein, acetyl coenzyme A carboxylase, and fatty acid synthase. All HF/HC-fed mice developed insulin resistance, the magnitude being lower in ALR-H-KO mice. HF/HC-fed ALR-H-HET mice were more resistant to glucose challenge than WT or ALR-H-KO mice. The frequency of tumor necrosis factor alpha-producing, interleukin 6 (IL6)-producing, and IL17-producing cells was greater in ALR-H-KO than ALR-H-HET and lowest in WT mice. HF/HC feeding did not increase their number in ALR-H-KO mice, and the increase in ALR-H-HET was greater than that in WT mice except for IL17 cells. Cluster of differentiation 25-positive (CD25+ ) forkhead box P3-positive CD4+ regulatory T-cell frequency was lower in ALR-H-HET than WT mice and further reduced in ALR-H-KO mice; HF/HC reduced regulatory T-cell frequency only in WT mice. HF/HC-fed ALR-H-HET, but not WT, mice developed fibrosis; and ALR-H-KO mice progressed to cirrhosis. White adipose tissue of HF/HC-fed ALR-deficient mice developed strong inflammation, indicating bidirectional interactions with the liver. Hepatic and serum ALR levels were significantly reduced in patients with NASH-cirrhosis. Serum ALR was also significantly lower in patients with NASH.CONCLUSIONS:
Hepatic ALR deficiency may be a critical predisposing factor for aggressive NAFLD progression.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro
/
Enfermedad del Hígado Graso no Alcohólico
/
Hígado
/
Cirrosis Hepática
Tipo de estudio:
Etiology_studies
/
Observational_studies
/
Prognostic_studies
Idioma:
En
Revista:
Hepatology
Año:
2020
Tipo del documento:
Article