Inhibition of Ubiquitin Ligase F-box and WD Repeat Domain-containing 7α (Fbw7α) Causes Hepatosteatosis through Krüppel-like Factor 5 (KLF5)/Peroxisome Proliferator-activated Receptor γ2 (PPARγ2) Pathway but Not SREBP-1c Protein in Mice

Abstract

F-box and WD repeat domain-containing 7 (Fbw7) is the component of an evolutionarily conserved complex of the Skp1-Cul1-F-box protein ubiquitin ligase and is involved in substrate recognition of the complex (1, 2). Fbw7 targets several proto-oncogenes that function in cell growth and division pathways, including c-Myc (encoded by Myc), cyclin E, Notch, and c-Jun (encoded by Jun) (3-7). Fbw7 is perturbed in many human malignancies and is an established tumor suppressor (8 -11). Mouse Fbw7 exists in three different isoforms as follows: ␣, ␤, and ␥. The ␣ isoform is expressed ubiquitously, whereas the ␤ and ␥ isoforms are expressed restrictedly in the brain, heart, testis, and skeletal muscle (12). Intriguing characteristics of Fbw7␣ (encoded by the isoform1 of Fbxw7) have recently been described by Ericsson et al. (13) who demonstrated that this cell growth regulator also regulated the degradation of the nuclear forms of the sterol regulatory elementbinding protein (SREBP) 2 family (14). SREBPs, belonging to the bHLH-Zip transcription factor family, are established regulators of lipid synthesis. The unique features of SREBPs are their rough-surfaced endoplasmic reticulum membrane-bound transcription factors. These factors need to undergo proteolytic cleavage for nuclear transport to activate the expression of genes involved in lipid synthesis. This represents the crucial step for sterol and fatty acid synthetic gene regulation (15)(16)(17). The SREBP family includes three isoforms as follows: . SREBP-2 governs cellular sterol regulation, whereas hepatic SREBP-1c (encoded by the isoformb of Srebf1) controls fatty acid and triglyceride synthesis depending on the nutritional state of the liver. SREBP-1a is highly expressed in growing cells and contributes to the synthesis of cholesterol, triglyceride (TG), and phospholipid for the supply of membrane lipids during cell growth (21, 22). Nuclear SREBP-1a regulates the cell cycle and growth by itself, indicating its strong association with cell growth (23,24).Without a proteasome inhibitor such as calpain inhibitor I in cell cultures, nuclear SREBPs are rapidly degraded by the ubiquitin-proteasome pathway after cleavage. Recently, Fbw7 was reported to be the key factor for this degradation of SREBPs in cultured cells (14). SREBP-1a is phosphorylated at several sites * This work was supported by grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan. □ S The on-line version of this article (available at http://www.jbc.org) contains supplemental

Circadian Amplitude Regulation via FBXW7-Targeted REV-ERBα Degradation

“…FBXW7 has been previously implicated in hepatic triglyceride metabolism (Kumadaki et al, 2011; Onoyama et al, 2011), but the mechanism has been controversial. Our work, in conjunction with previous ChIP studies (Bugge et al, 2012; Cho et al, 2012) suggests that the post-translational control of REV-ERBα stability and thereby circadian clock output gene expression is a critical factor contributing to liver metabolic homeostasis.…”

Expanding Roles for SREBP in Metabolism

“…In the absence of Akt signaling, GSK3 phosphorylates SREBP leading to ubiquitinylation by the SCF(Fbw7) ubiquitin ligase and proteasomal degradation of the active transcription factor. While liver-specific knockout of Fbw7 in mice resulted in steatohepatitis, the observed accumulation of liver triglyceride does not require SREBP-1, suggesting that this Fbw7 degradative mechanism may function in non-hepatic tissues (Kumadaki et al, 2011). The nutrient sensor AMP-activated protein kinase (AMPK) negatively regulates SREBP to limit lipogenesis under nutrient-limiting conditions by directly phosphorylating SREBP (Li et al, 2011).…”

F-box and WD Repeat Domain-containing-7 (Fbxw7) Protein Targets Endoplasmic Reticulum-anchored Osteogenic and Chondrogenic Transcriptional Factors for Degradation

“…Inactivation of Fbxw7 in mouse preadipocytes or adult human mesenchymal stem cells promotes their differentiation into mature adipocytes (31,32). Genetic ablation or RNAi-mediated depletion of Fbxw7 in mouse liver induced fatty liver, reminiscent of that associated with nonalcoholic steatohepatitis in humans (29,30). Fbxw7 also targets peroxisome proliferator-activated receptor ␥ (PPAR␥) coactivator 1␣ (PGC-1␣) for degradation (47), although the relationship between Fbxw7 and PGC-1␣ in adipogenesis or lipogenesis remains to be determined.…”

“…Conditional ablation of Fbxw7 in the liver results both in a shift in the differentiation of liver stem cells from the he-patocyte lineage to cholangiocytes as well as in increased cell proliferation (29). Liver-specific deficiency of Fbxw7 also results in lipid accumulation in hepatocytes as a consequence of the accumulation of its targets KLF5 and sterol response element-binding proteins (SREBPs) (29,30). In cultured cells, Fbxw7 deficiency promotes the formation of lipid droplets as a result of the accumulation of SREBPs and CCAAT/enhancerbinding protein ␣ (c/EBP␣) (31,32).…”