SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome.

Acetylation is increasingly recognized as an important metabolic regulatory posttranslational protein modification, yet the metabolic consequence of mitochondrial protein hyperacetylation is unknown. We find that high-fat diet (HFD) feeding induces hepatic mitochondrial protein hyperacetylation in mice and downregulation of the major mitochondrial protein deacetylase SIRT3. Mice lacking SIRT3 (SIRT3KO) placed on a HFD show accelerated obesity, insulin resistance, hyperlipidemia, and steatohepatitis compared to wild-type (WT) mice. The lipogenic enzyme stearoyl-CoA desaturase 1 is highly induced in SIRT3KO mice, and its deletion rescues both WT and SIRT3KO mice from HFD-induced hepatic steatosis and insulin resistance. We further identify a single nucleotide polymorphism in the human SIRT3 gene that is suggestive of a genetic association with the metabolic syndrome. This polymorphism encodes a point mutation in the SIRT3 protein, which reduces its overall enzymatic efficiency. Our findings show that loss of SIRT3 and dysregulation of mitochondrial protein acetylation contribute to the metabolic syndrome.

Nuclear export of histone deacetylase 7 during thymic selection is required for immune self-tolerance.

Histone deacetylase 7 (HDAC7) is a T-cell receptor (TCR) signal-dependent regulator of differentiation that is highly expressed in CD4/CD8 double-positive (DP) thymocytes. Here, we examine the effect of blocking TCR-dependent nuclear export of HDAC7 during thymic selection, through expression of a signal-resistant mutant of HDAC7 (HDAC7-ΔP) in thymocytes. We find that HDAC7-ΔP transgenic thymocytes exhibit a profound block in negative thymic selection, but can still undergo positive selection, resulting in the escape of autoreactive T cells into the periphery. Gene expression profiling reveals a comprehensive suppression of the negative selection-associated gene expression programme in DP thymocytes, associated with a defect in the activation of MAP kinase pathways by TCR signals. The consequence of this block in vivo is a lethal autoimmune syndrome involving the exocrine pancreas and other abdominal organs. These experiments establish a novel molecular model of autoimmunity and cast new light on the relationship between thymic selection and immune self-tolerance.

Histone deacetylase 7 regulates cell survival and TCR signaling in CD4/CD8 double-positive thymocytes.

CD4/CD8 double-positive thymocytes express the transcriptional repressor histone deacetylase (HDAC)7, a class IIa HDAC that is exported from the cell nucleus after TCR engagement. Through signal-dependent nuclear export, class IIa HDACs such as HDAC7 mediate signal-dependent changes in gene expression that are important to developmental fate decisions in multiple tissues. We report that HDAC7 is exported from the cell nucleus during positive selection in mouse thymocytes and that it regulates genes mediating the coupling between TCR engagement and downstream events that determine cell survival. Thymocytes lacking HDAC7 are inefficiently positively selected due to a severely shortened lifespan and exhibit a truncated repertoire of TCR Jα segments. The expression of multiple important mediators and modulators of the response to TCR engagement is altered in HDAC7-deficient thymocytes, resulting in increased tonic MAPK activity that contributes to the observed loss of viability. Remarkably, the activity of protein kinase D, the kinase that mediates nuclear export of HDAC7 in response to TCR signaling, is also increased in HDAC7-deficient thymocytes, suggesting that HDAC7 nuclear export governs a self-sustaining autoexcitatory loop. These experiments add to the understanding of the life/death decision in thymic T cell development, define a novel function for class IIa HDACs, and point to a novel feed-forward mechanism whereby these molecules regulate their own state and mediate stable developmental transitions.

KDM2A Deficiency in the Liver Promotes Abnormal Liver Function and Potential Liver Damage.

Dysregulation of metabolic functions in the liver impacts the development of diabetes and metabolic disorders. Normal liver function can be compromised by increased inflammation via the activation of signaling such as nuclear factor (NF)-κB signaling. Notably, we have previously identified lysine demethylase 2A (KDM2A)-as a critical negative regulator of NF-κB. However, there are no studies demonstrating the effect of KDM2A on liver function. Here, we established a novel liver-specific Kdm2a knockout mouse model to evaluate KDM2A's role in liver functions. An inducible hepatic deletion of Kdm2a, Alb-Cre-Kdm2afl/fl (Kdm2a KO), was generated by crossing the Kdm2a floxed mice (Kdm2afl/fl) we established with commercial albumin-Cre transgenic mice (B6.Cg-Tg(Alb-cre)21Mgn/J). We show that under a normal diet, Kdm2a KO mice exhibited increased serum alanine aminotransferase (ALT) activity, L-type triglycerides (TG) levels, and liver glycogen levels vs. WT (Kdm2afl/fl) animals. These changes were further enhanced in Kdm2a liver KO mice in high-fat diet (HFD) conditions. We also observed a significant increase in NF-κB target gene expression in Kdm2a liver KO mice under HFD conditions. Similarly, the KO mice exhibited increased immune cell infiltration. Collectively, these data suggest liver-specific KDM2A deficiency may enhance inflammation in the liver, potentially through NF-κB activation, and lead to liver dysfunction. Our study also suggests that the established Kdm2afl/fl mouse model may serve as a powerful tool for studying liver-related metabolic diseases.

Shining a Light on Alzheimer Disease and Other Dementias.

Bringing awareness to this major public health issue.

The Top Health Care Stories of 2019: Women's Reproductive Health.

U.S. maternal mortality rate continues to rise; women's abortion rights are challenged.

A Nurse in the House.

Freshman congresswoman Lauren Underwood brings nursing and health care policy experience to the table.

The Power of Silence.

'The Pause' honors patients who have passed and the medical team that cared for them.

The 'IT' Nurse.

For more than 30 years, Judy Murphy has been a leader in nursing informatics.

Those Who Comfort Us.

Updated several times a week with posts by a wide variety of authors, AJN's blog Off the Charts allows us to provide more timely-and often more personal-perspectives on professional, policy, and clinical issues. Best of the Blog will be a regular column to draw the attention of AJN readers to posts we think deserve a wider audience. To read more, please visit: www.ajnoffthecharts.com.

Empowering Nurses Across the Globe.

As the largest part of the health care workforce, it's nurses, says Leslie Mancuso, who will make the difference.

Integrating Mental Health into Primary Care.

As part of its Raise the Voice campaign to showcase nurses who are key players in transforming health care, the American Academy of Nursing has identified nurses they call edge runners-"practical innovators who have led the way in bringing new thinking and new methods to a wide range of health care challenges." This is the seventh in AJN's series of profiles of these nursing innovators. Read and be proud of what nurses can accomplish.

Partnering with the Police.

A nurse-led initiative trains law enforcement to effectively interact with people with mental illness.

Just Breathe: A Nurse's Tough Love Proves Crucial During One Mother's Labor.

Updated several times a week with posts by a wide variety of authors, AJN's blog Off the Charts allows us to provide more timely-and often more personal-perspectives on professional, policy, and clinical issues. Best of the Blog will be a regular column to bring AJN readers recent posts that we think deserve a wider audience. To read more, please visit: www.ajnoffthecharts.com.

Peace and Reconciliation.

Susan Schnall speaks about the lingering effects of Agent Orange-and what remains to be done about them.

Concomitants of alcoholism: differential effects of thiamine deficiency, liver damage, and food deprivation on the rat brain in vivo.

RATIONALE: Serious neurological concomitants of alcoholism include Wernicke's encephalopathy (WE), Korsakoff's syndrome (KS), and hepatic encephalopathy (HE). OBJECTIVES: This study was conducted in animal models to determine neuroradiological signatures associated with liver damage caused by carbon tetrachloride (CCl4), thiamine deficiency caused by pyrithiamine treatment, and nonspecific nutritional deficiency caused by food deprivation. METHODS: Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) were used to evaluate brains of wild-type Wistar rats at baseline and following treatment. RESULTS: Similar to observations in ethanol (EtOH) exposure models, thiamine deficiency caused enlargement of the lateral ventricles. Liver damage was not associated with effects on cerebrospinal fluid volumes, whereas food deprivation caused modest enlargement of the cisterns. In contrast to what has repeatedly been shown in EtOH exposure models, in which levels of choline-containing compounds (Cho) measured by MRS are elevated, Cho levels in treated animals in all three experiments (i.e., liver damage, thiamine deficiency, and food deprivation) were lower than those in baseline or controls. CONCLUSIONS: These results add to the growing body of literature suggesting that MRS-detectable Cho is labile and can depend on a number of variables that are not often considered in human experiments. These results also suggest that reductions in Cho observed in humans with alcohol use disorder (AUD) may well be due to mild manifestations of concomitants of AUD such as liver damage or nutritional deficiencies and not necessarily to alcohol consumption per se.

'Centering' care.

As part of its Raise the Voice campaign to showcase nurses who are key players in transforming health care, the American Academy of Nursing has identified nurses they call edge runners -"practical innovators who have led the way in bringing new thinking and new methods to a wide range of health care challenges." This is the fifth in AJN's series of profiles of these nursing innovators. Read and be proud of what nurses can accomplish.

The quintessential nursing population.

A past nursing model for 'chronically critically ill' patients provides lessons for health care today.As part of its Raise the Voice campaign to showcase nurses who are key players in transforming health care, the American Academy of Nursing has identified nurses they call edge runners-"practical innovators who have led the way in bringing new thinking and new methods to a wide range of health care challenges." This is the fourth in AJN's series of profiles of these nursing innovators. Read and be proud of what nurses can accomplish.

Caring for the whole person.

A nurse-managed health care network offers 'one-stop shopping' for low-income patients.As part of its Raise the Voice campaign to showcase nurses who are key players in transforming health care, the American Academy of Nursing has identified nurses they call edge runners-"practical innovators who have led the way in bringing new thinking and new methods to a wide range of health care challenges." This is the third in AJN's series of profiles of these nursing innovators. Read and be proud of what nurses can accomplish.

Promoting community health.

A nurse-managed health center bridges the gap to care.