The PNPLA3 I148M variant increases ketogenesis and decreases hepatic de novo lipogenesis and mitochondrial function in humans
Cell Metab. 2023 Oct 20:S1550-4131(23)00377-7. doi: 10.1016/j.cmet.2023.10.008. Online ahead of print.ABSTRACTThe PNPLA3 I148M variant is the major genetic risk factor for all stages of fatty liver disease, but the underlying pathophysiology remains unclear. We studied the effect of this variant on hepatic metabolism in homozygous carriers and non-carriers under multiple physiological conditions with state-of-the-art stable isotope techniques. After an overnight fast, carriers had higher plasma β-hydroxybutyrate concentrations and lower hepatic de novo lipogenesis (DNL) compared to non-carriers. After a mixed meal, fatty ...
Source: Cell Metabolism - November 1, 2023 Category: Cytology Authors: Panu K Luukkonen Kimmo Porthan Noora Ahlholm Fredrik Rosqvist Sylvie Dufour Xian-Man Zhang Tiina E Lehtim äki Wenla Sepp änen Marju Orho-Melander Leanne Hodson Kitt Falk Petersen Gerald I Shulman Hannele Yki-J ärvinen Source Type: research

Hyperinsulinemia acts via acinar insulin receptors to initiate pancreatic cancer by increasing digestive enzyme production and inflammation
Cell Metab. 2023 Oct 26:S1550-4131(23)00372-8. doi: 10.1016/j.cmet.2023.10.003. Online ahead of print.ABSTRACTThe rising pancreatic cancer incidence due to obesity and type 2 diabetes is closely tied to hyperinsulinemia, an independent cancer risk factor. Previous studies demonstrated reducing insulin production suppressed pancreatic intraepithelial neoplasia (PanIN) pre-cancerous lesions in Kras-mutant mice. However, the pathophysiological and molecular mechanisms remained unknown, and in particular it was unclear whether hyperinsulinemia affected PanIN precursor cells directly or indirectly. Here, we demonstrate that ins...
Source: Cell Metabolism - November 1, 2023 Category: Cytology Authors: Anni M Y Zhang Yi Han Xia Jeffrey S H Lin Ken H Chu Wei Chuan K Wang Titine J J Ruiter Jenny C C Yang Nan Chen Justin Chhuor Shilpa Patil Haoning Howard Cen Elizabeth J Rideout Vincent R Richard David F Schaeffer Rene P Zahedi Christoph H Borchers James D Source Type: research

The PNPLA3 I148M variant increases ketogenesis and decreases hepatic de novo lipogenesis and mitochondrial function in humans
Cell Metab. 2023 Oct 20:S1550-4131(23)00377-7. doi: 10.1016/j.cmet.2023.10.008. Online ahead of print.ABSTRACTThe PNPLA3 I148M variant is the major genetic risk factor for all stages of fatty liver disease, but the underlying pathophysiology remains unclear. We studied the effect of this variant on hepatic metabolism in homozygous carriers and non-carriers under multiple physiological conditions with state-of-the-art stable isotope techniques. After an overnight fast, carriers had higher plasma β-hydroxybutyrate concentrations and lower hepatic de novo lipogenesis (DNL) compared to non-carriers. After a mixed meal, fatty ...
Source: Cell Metabolism - November 1, 2023 Category: Cytology Authors: Panu K Luukkonen Kimmo Porthan Noora Ahlholm Fredrik Rosqvist Sylvie Dufour Xian-Man Zhang Tiina E Lehtim äki Wenla Sepp änen Marju Orho-Melander Leanne Hodson Kitt Falk Petersen Gerald I Shulman Hannele Yki-J ärvinen Source Type: research

Hyperinsulinemia acts via acinar insulin receptors to initiate pancreatic cancer by increasing digestive enzyme production and inflammation
Cell Metab. 2023 Oct 26:S1550-4131(23)00372-8. doi: 10.1016/j.cmet.2023.10.003. Online ahead of print.ABSTRACTThe rising pancreatic cancer incidence due to obesity and type 2 diabetes is closely tied to hyperinsulinemia, an independent cancer risk factor. Previous studies demonstrated reducing insulin production suppressed pancreatic intraepithelial neoplasia (PanIN) pre-cancerous lesions in Kras-mutant mice. However, the pathophysiological and molecular mechanisms remained unknown, and in particular it was unclear whether hyperinsulinemia affected PanIN precursor cells directly or indirectly. Here, we demonstrate that ins...
Source: Cell Metabolism - November 1, 2023 Category: Cytology Authors: Anni M Y Zhang Yi Han Xia Jeffrey S H Lin Ken H Chu Wei Chuan K Wang Titine J J Ruiter Jenny C C Yang Nan Chen Justin Chhuor Shilpa Patil Haoning Howard Cen Elizabeth J Rideout Vincent R Richard David F Schaeffer Rene P Zahedi Christoph H Borchers James D Source Type: research

The PNPLA3 I148M variant increases ketogenesis and decreases hepatic de novo lipogenesis and mitochondrial function in humans
Cell Metab. 2023 Oct 20:S1550-4131(23)00377-7. doi: 10.1016/j.cmet.2023.10.008. Online ahead of print.ABSTRACTThe PNPLA3 I148M variant is the major genetic risk factor for all stages of fatty liver disease, but the underlying pathophysiology remains unclear. We studied the effect of this variant on hepatic metabolism in homozygous carriers and non-carriers under multiple physiological conditions with state-of-the-art stable isotope techniques. After an overnight fast, carriers had higher plasma β-hydroxybutyrate concentrations and lower hepatic de novo lipogenesis (DNL) compared to non-carriers. After a mixed meal, fatty ...
Source: Cell Metabolism - November 1, 2023 Category: Cytology Authors: Panu K Luukkonen Kimmo Porthan Noora Ahlholm Fredrik Rosqvist Sylvie Dufour Xian-Man Zhang Tiina E Lehtim äki Wenla Sepp änen Marju Orho-Melander Leanne Hodson Kitt Falk Petersen Gerald I Shulman Hannele Yki-J ärvinen Source Type: research

Hyperinsulinemia acts via acinar insulin receptors to initiate pancreatic cancer by increasing digestive enzyme production and inflammation
Cell Metab. 2023 Oct 26:S1550-4131(23)00372-8. doi: 10.1016/j.cmet.2023.10.003. Online ahead of print.ABSTRACTThe rising pancreatic cancer incidence due to obesity and type 2 diabetes is closely tied to hyperinsulinemia, an independent cancer risk factor. Previous studies demonstrated reducing insulin production suppressed pancreatic intraepithelial neoplasia (PanIN) pre-cancerous lesions in Kras-mutant mice. However, the pathophysiological and molecular mechanisms remained unknown, and in particular it was unclear whether hyperinsulinemia affected PanIN precursor cells directly or indirectly. Here, we demonstrate that ins...
Source: Cell Metabolism - November 1, 2023 Category: Cytology Authors: Anni M Y Zhang Yi Han Xia Jeffrey S H Lin Ken H Chu Wei Chuan K Wang Titine J J Ruiter Jenny C C Yang Nan Chen Justin Chhuor Shilpa Patil Haoning Howard Cen Elizabeth J Rideout Vincent R Richard David F Schaeffer Rene P Zahedi Christoph H Borchers James D Source Type: research

The PNPLA3 I148M variant increases ketogenesis and decreases hepatic de novo lipogenesis and mitochondrial function in humans
Cell Metab. 2023 Oct 20:S1550-4131(23)00377-7. doi: 10.1016/j.cmet.2023.10.008. Online ahead of print.ABSTRACTThe PNPLA3 I148M variant is the major genetic risk factor for all stages of fatty liver disease, but the underlying pathophysiology remains unclear. We studied the effect of this variant on hepatic metabolism in homozygous carriers and non-carriers under multiple physiological conditions with state-of-the-art stable isotope techniques. After an overnight fast, carriers had higher plasma β-hydroxybutyrate concentrations and lower hepatic de novo lipogenesis (DNL) compared to non-carriers. After a mixed meal, fatty ...
Source: Cell Metabolism - November 1, 2023 Category: Cytology Authors: Panu K Luukkonen Kimmo Porthan Noora Ahlholm Fredrik Rosqvist Sylvie Dufour Xian-Man Zhang Tiina E Lehtim äki Wenla Sepp änen Marju Orho-Melander Leanne Hodson Kitt Falk Petersen Gerald I Shulman Hannele Yki-J ärvinen Source Type: research

Dynamic scRNA-seq of live human pancreatic slices reveals functional endocrine cell neogenesis through an intermediate ducto-acinar stage
This study provides the first longitudinal scRNA-seq analysis of whole human pancreatic tissue, confirming its plasticity in a dynamic fashion.PMID:37898119 | DOI:10.1016/j.cmet.2023.10.001 (Source: Cell Metabolism)
Source: Cell Metabolism - October 28, 2023 Category: Cytology Authors: Mayur Doke Silvia Álvarez-Cubela Dagmar Klein Isabella Altilio Joseph Schulz Luciana Mateus Gon çalves Joana Alma ça Christopher A Fraker Alberto Pugliese Camillo Ricordi Mirza M F Qadir Ricardo L Pastori Juan Dom ínguez-Bendala Source Type: research

Dynamic scRNA-seq of live human pancreatic slices reveals functional endocrine cell neogenesis through an intermediate ducto-acinar stage
This study provides the first longitudinal scRNA-seq analysis of whole human pancreatic tissue, confirming its plasticity in a dynamic fashion.PMID:37898119 | DOI:10.1016/j.cmet.2023.10.001 (Source: Cell Metabolism)
Source: Cell Metabolism - October 28, 2023 Category: Cytology Authors: Mayur Doke Silvia Álvarez-Cubela Dagmar Klein Isabella Altilio Joseph Schulz Luciana Mateus Gon çalves Joana Alma ça Christopher A Fraker Alberto Pugliese Camillo Ricordi Mirza M F Qadir Ricardo L Pastori Juan Dom ínguez-Bendala Source Type: research

Dynamic scRNA-seq of live human pancreatic slices reveals functional endocrine cell neogenesis through an intermediate ducto-acinar stage
This study provides the first longitudinal scRNA-seq analysis of whole human pancreatic tissue, confirming its plasticity in a dynamic fashion.PMID:37898119 | DOI:10.1016/j.cmet.2023.10.001 (Source: Cell Metabolism)
Source: Cell Metabolism - October 28, 2023 Category: Cytology Authors: Mayur Doke Silvia Álvarez-Cubela Dagmar Klein Isabella Altilio Joseph Schulz Luciana Mateus Gon çalves Joana Alma ça Christopher A Fraker Alberto Pugliese Camillo Ricordi Mirza M F Qadir Ricardo L Pastori Juan Dom ínguez-Bendala Source Type: research

Tyrosine catabolism enhances genotoxic chemotherapy by suppressing translesion DNA synthesis in epithelial ovarian cancer
Cell Metab. 2023 Oct 19:S1550-4131(23)00371-6. doi: 10.1016/j.cmet.2023.10.002. Online ahead of print.ABSTRACTAmino acid metabolism has been actively investigated as a potential target for antitumor therapy, but how it may alter the response to genotoxic chemotherapy remains largely unknown. Here, we report that the depletion of fumarylacetoacetate hydrolase (FAH), an enzyme that catalyzes the final step of tyrosine catabolism, reduced chemosensitivity in epithelial ovarian cancer (EOC). The expression level of FAH correlated significantly with chemotherapy efficacy in patients with EOC. Mechanistically, under genotoxic ch...
Source: Cell Metabolism - October 27, 2023 Category: Cytology Authors: Jie Li Cuimiao Zheng Qiuwen Mai Xi Huang Wenfeng Pan Jingyi Lu Zhengfan Chen Suman Zhang Chunyu Zhang Hua Huang Yangyang Chen Hongbo Guo Zhenyin Wu Chunnuan Deng Yiting Jiang Bo Li Junxiu Liu Shuzhong Yao Chaoyun Pan Source Type: research

Functional interrogation of twenty type 2 diabetes-associated genes using isogenic human embryonic stem cell-derived β-like cells
We examined the impacts of each knockout on β cell differentiation, functions, and survival. We generated gene expression and chromatin accessibility profiles on β cells derived from each knockout line. Analyses of T2D-association signals overlapping HNF4A-dependent ATAC peaks identified a likely causal variant at the FAIM2 T2D-association signal. Additionally, the integrative association analyses identified four genes (CP, RNASE1, PCSK1N, and GSTA2) associated with insulin production, and two genes (TAGLN3 and DHRS2) associated with β cell sensitivity to lipotoxicity. Finally, we leveraged deep ATAC-seq read coverage t...
Source: Cell Metabolism - October 20, 2023 Category: Cytology Authors: Dongxiang Xue Narisu Narisu D Leland Taylor Meili Zhang Caleb Grenko Henry J Taylor Tingfen Yan Xuming Tang Neelam Sinha Jiajun Zhu J Jeya Vandana Angie Chi Nok Chong Angela Lee Erin C Mansell Amy J Swift Michael R Erdos Aaron Zhong Lori L Bonnycastle Tin Source Type: research

Dietary fructose-mediated adipocyte metabolism drives antitumor CD8 < sup > + < /sup > T  cell responses
Cell Metab. 2023 Oct 15:S1550-4131(23)00367-4. doi: 10.1016/j.cmet.2023.09.011. Online ahead of print.ABSTRACTFructose consumption is associated with tumor growth and metastasis in mice, yet its impact on antitumor immune responses remains unclear. Here, we show that dietary fructose modulates adipocyte metabolism to enhance antitumor CD8+ T cell immune responses and control tumor growth. Transcriptional profiling of tumor-infiltrating CD8+ T cells reveals that dietary fructose mediates attenuated transition of CD8+ T cells to terminal exhaustion, leading to a superior antitumor efficacy. High-fructose feeding initiates ad...
Source: Cell Metabolism - October 20, 2023 Category: Cytology Authors: Yuerong Zhang Xiaoyan Yu Rujuan Bao Haiyan Huang Chuanjia Gu Qianming Lv Qiaoqiao Han Xian Du Xu-Yun Zhao Youqiong Ye Ren Zhao Jiayuan Sun Qiang Zou Source Type: research

Functional interrogation of twenty type 2 diabetes-associated genes using isogenic human embryonic stem cell-derived β-like cells
We examined the impacts of each knockout on β cell differentiation, functions, and survival. We generated gene expression and chromatin accessibility profiles on β cells derived from each knockout line. Analyses of T2D-association signals overlapping HNF4A-dependent ATAC peaks identified a likely causal variant at the FAIM2 T2D-association signal. Additionally, the integrative association analyses identified four genes (CP, RNASE1, PCSK1N, and GSTA2) associated with insulin production, and two genes (TAGLN3 and DHRS2) associated with β cell sensitivity to lipotoxicity. Finally, we leveraged deep ATAC-seq read coverage t...
Source: Cell Metabolism - October 20, 2023 Category: Cytology Authors: Dongxiang Xue Narisu Narisu D Leland Taylor Meili Zhang Caleb Grenko Henry J Taylor Tingfen Yan Xuming Tang Neelam Sinha Jiajun Zhu J Jeya Vandana Angie Chi Nok Chong Angela Lee Erin C Mansell Amy J Swift Michael R Erdos Aaron Zhong Lori L Bonnycastle Tin Source Type: research

Dietary fructose-mediated adipocyte metabolism drives antitumor CD8 < sup > + < /sup > T  cell responses
Cell Metab. 2023 Oct 15:S1550-4131(23)00367-4. doi: 10.1016/j.cmet.2023.09.011. Online ahead of print.ABSTRACTFructose consumption is associated with tumor growth and metastasis in mice, yet its impact on antitumor immune responses remains unclear. Here, we show that dietary fructose modulates adipocyte metabolism to enhance antitumor CD8+ T cell immune responses and control tumor growth. Transcriptional profiling of tumor-infiltrating CD8+ T cells reveals that dietary fructose mediates attenuated transition of CD8+ T cells to terminal exhaustion, leading to a superior antitumor efficacy. High-fructose feeding initiates ad...
Source: Cell Metabolism - October 20, 2023 Category: Cytology Authors: Yuerong Zhang Xiaoyan Yu Rujuan Bao Haiyan Huang Chuanjia Gu Qianming Lv Qiaoqiao Han Xian Du Xu-Yun Zhao Youqiong Ye Ren Zhao Jiayuan Sun Qiang Zou Source Type: research