Lack of Augmenter of Liver Regeneration Disrupts Cholesterol Homeostasis of Liver in Mice by Inhibiting the AMPK Pathway

Abstract

It is well known that excessive cholesterol accumulation within hepatocytes deteriorates nonalcoholic fatty liver disease (NAFLD). Augmenter of liver regeneration (ALR) has been reported to alleviate NAFLD through anti‐apoptosis; however, whether ALR could protect liver from cholesterol‐induced NAFLD remains unclear. Mice with heterozygous deletion of Gfer (the gene for ALR, Gfer +/− ) were generated, and liver steatosis was induced by either choline‐deficient ethionine‐supplemented, methionine choline–deficient diet for 4 weeks, or high‐fat diet for 16 weeks. The results showed that Gfer +/− mice developed a more severe fatty liver phenotype than Gfer +/+ mice. The livers of Gfer +/− mice exhibited a higher concentration of cholesterol and low‐density lipoprotein compared with the normal mice. Transcriptome‐based analysis predicts low‐density lipoprotein receptor (LDLR) primarily involved in the metabolic pathway. The experiments further indicate that cholesterol accumulation within hepatocytes is closely associated with enhancing the expression of LDLR and activation of sterol regulatory element binding protein 2 (SREBP2). Because adenosine monophosphate–activated protein kinase (AMPK) is a critical regulator of SREBP2 activation, we measured whether the activity of AMPK was regulated by ALR. We found that knockdown of ALR expression inhibited the phosphorylation of LKB1, an upstream activator of AMPK, followed by AMPK inactivation and SREBP2 maturation/nuclear translocation, leading to extensive cholesterol accumulation. Meanwhile, cellular oxidative stress increased as a result of ALR knockdown, indicating that ALR might also have a role in suppressing reactive oxygen species production. Conclusion : Our results confirm that ALR regulates cholesterol metabolism and alleviates hepatic steatosis probably through the LKB1‐AMPK‐SREBP2‐LDLR pathway in vivo and in vitro , providing a putative mechanism for combating fatty liver disease.

Mammalian Ste20-Like Kinase 1 Regulates AMPK to Mitigate the Progression of Non-Alcoholic Fatty Liver Disease

“…These ndings are consistent with prior research by other investigators. 31,[45][46][47] By inducing MST1 overexpression in in vivo and in vitro models, we have elucidated that MST1 phosphorylates AMPKα at Thr172, leading to a cascade of changes in the AMPK/SREBP2 signaling pathway. This modulation affects SREBP2 nuclear translocation and alters the expression of SREBP2 and downstream target genes HMGCR and HMGCS1.…”

Augmenter of liver regeneration: Mitochondrial function and steatohepatitis

“…16 A study published concurrently also reported increased SREBP2 expression and cholesterol accumulation in global ALR-HET mice. 99 The authors went on to show inactivation of adenosine monophosphate-activated protein kinase (AMPK) as a mechanism of increased cholesterol in high-fat diet-fed ALR-HET mice.…”

The protective roles of augmenter of liver regeneration in hepatocytes in the non-alcoholic fatty liver disease

“…The FAD-dependent sulfhydryl oxidase activity of ALR allows it to enhance the oxidative phosphorylation capacity of mitochondria ( Daithankar et al, 2009 ). Compelling evidence indicates that ALR inhibits apoptosis, promotes hepatocyte regeneration, and prohibits fibrotic progression in various murine models of NAFLD ( Xiao et al, 2015 ; Xu et al, 2016 ; Weiss et al, 2017 ; Kumar et al, 2020 ; Wang et al, 2020 ). All these beneficial effects of ALR in hepatocytes are directly or indirectly related to its regulation of mitochondria.…”

“…SREBP2 and low-density lipoprotein receptor actions are closely associated with cholesterol accumulation within hepatocytes. Thus, alterations in these events can lead to extensive cholesterol accumulation and the development of lipid metabolism disorders ( Wang et al, 2020 ).…”