Pleiotropic actions of IP6K1 mediate hepatic metabolic dysfunction to promote nonalcoholic fatty liver disease and steatohepatitis

Mukherjee, Sandip; Chakraborty, Molee; Ulmasov, Barbara; McCommis, Kyle S.; Zhang, Jinsong; Carpenter, Danielle; Msengi, Eliwaza Naomi; Haubner, Jake; Guo, Chun; Pike, Daniel P.; Ghoshal, Sakti Prasad; Ford, David A.; Neuschwander‐Tetri, Brent A.; Chakraborty, Anutosh

doi:10.1016/j.molmet.2021.101364

Cited by 10 publications

(46 citation statements)

References 70 publications

(132 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…BP356-100) (2.0 g/kg body weight, ip). Blood glucose levels were measured at the indicated time periods …”

Section: Methodsmentioning

confidence: 99%

“…Liver was processed for histological studies. These studies were performed following our standardized procedures. , …”

Section: Methodsmentioning

confidence: 99%

“…11,12,15 Furthermore, whole body-or hepatocyte-specific Ip6k1 deletion ameliorates NAFLD and NASH in mice. 22 Ip6k2 deletion in mice decreases cancer cell migration, invasion, and tumor metastasis. 21 Deletion of Ip6k3 protects mice from age-induced fat accumulation and insulin resistance.…”

Section: ■ Introductionmentioning

confidence: 98%

“…The inositol pyrophosphate (PP-InsP) biosynthetic pathway is a promising target in metabolic diseases, osteoporosis, thromboembolism, infection, cancer metastasis, and aging. − Inositol pyrophosphates are conserved eukaryotic messenger molecules with functionally significant and highly “energetic” diphosphate groups. , They play crucial roles in diverse cellular functions including insulin secretion and signaling, ,, ATP production, and DNA damage sensing and repair . Many of these effects contribute to an overarching role for PP-InsPs in regulating bioenergetic homeostasis. ,, The initial and primary reaction in the PP-InsP synthetic pathway is the phosphorylation of inositol hexakisphosphate (InsP 6 ) to 5-diphosphoinositol pentakisphosphate (5-InsP 7 ) by a family of small molecule kinases known as IP6K1, IP6K2, and IP6K3.…”

Section: Introductionmentioning

confidence: 99%

“…IP6K1 and IP6K2 are expressed in most tissues while IP6K3 is mainly expressed in heart, skeletal muscle, and brain. , IP6K1 regulates metabolism in vivo by several mechanisms. , This isoform promotes insulin secretion from pancreatic β cells but attenuates certain aspects of insulin signaling . Moreover, IP6K1 reduces whole-body energy expenditure by inhibiting adipocyte thermogenesis. , Consequently, whole body and adipocyte specific Ip6k1-KO mice display increased insulin sensitivity and energy expenditure and are protected from high fat diet (HFD)-induced obesity, hyperinsulinemia, and insulin resistance. ,, Furthermore, whole body- or hepatocyte-specific Ip6k1 deletion ameliorates NAFLD and NASH in mice .…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Development of Novel IP6K Inhibitors for the Treatment of Obesity and Obesity-Induced Metabolic Dysfunctions

et al. 2022

Self Cite

View full text Add to dashboard Cite

Obesity and obesity-induced metabolic dysfunctions are significant risk factors for nonalcoholic fatty liver disease and cardiovascular diseases. Thus, obesity is an economic and social burden in developed countries. Blocking the synthesis of inositol pyrophosphates by inositol hexakisphosphate kinase (IP6K) has been identified as a potential therapeutic strategy for obesity and related diseases. We have developed a novel and potent IP6K inhibitor 20 (UNC7467) (IC50 values: IP6K1 8.9 nM; IP6K2 4.9 nM; IP6K3 1320 nM). Inositol phosphate profiling of the HCT116 colon cancer cell line demonstrates that 20 reduced levels of inositol pyrophosphates by 66–81%, without significantly perturbing levels of other inositol phosphates. Furthermore, intraperitoneal injection of 20 in diet-induced obese mice improved glycemic profiles, ameliorated hepatic steatosis, and reduced weight gain without altering food intake. Thus, inhibitor 20 can be used as an in vivo probe for IP6K-related research. Moreover, it may have therapeutic relevance in treating obesity and related diseases.

show abstract

“…BP356-100) (2.0 g/kg body weight, ip). Blood glucose levels were measured at the indicated time periods …”

Section: Methodsmentioning

confidence: 99%

“…Liver was processed for histological studies. These studies were performed following our standardized procedures. , …”

Section: Methodsmentioning

confidence: 99%