DEP domain-containing mTOR-interacting protein suppresses lipogenesis and ameliorates hepatic steatosis and acute-on-chronic liver injury in alcoholic liver disease.

Alcoholic liver disease (ALD) is characterized by lipid accumulation and liver injury. However, how chronic alcohol consumption causes hepatic lipid accumulation remains elusive. The present study demonstrates that activation of the mechanistic target of rapamycin complex 1 (mTORC1) plays a causal role in alcoholic steatosis, inflammation, and liver injury. Chronic-plus-binge ethanol feeding led to hyperactivation of mTORC1, as evidenced by increased phosphorylation of mTOR and its downstream kinase S6 kinase 1 (S6K1) in hepatocytes. Aberrant activation of mTORC1 was likely attributed to the defects of the DEP domain-containing mTOR-interacting protein (DEPTOR) and the nicotinamide adenine dinucleotide-dependent deacetylase sirtuin 1 (SIRT1) in the liver of chronic-plus-binge ethanol-fed mice and in the liver of patients with ALD. Conversely, adenoviral overexpression of hepatic DEPTOR suppressed mTORC1 signaling and ameliorated alcoholic hepatosteatosis, inflammation, and acute-on-chronic liver injury. Mechanistically, the lipid-lowering effect of hepatic DEPTOR was attributable to decreased proteolytic processing, nuclear translocation, and transcriptional activity of the lipogenic transcription factor sterol regulatory element-binding protein-1 (SREBP-1). DEPTOR-dependent inhibition of mTORC1 also attenuated alcohol-induced cytoplasmic accumulation of the lipogenic regulator lipin 1 and prevented alcohol-mediated inhibition of fatty acid oxidation. Pharmacological intervention with rapamycin alleviated the ability of alcohol to up-regulate lipogenesis, to down-regulate fatty acid oxidation, and to induce steatogenic phenotypes. Chronic-plus-binge ethanol feeding led to activation of SREBP-1 and lipin 1 through S6K1-dependent and independent mechanisms. Furthermore, hepatocyte-specific deletion of SIRT1 disrupted DEPTOR function, enhanced mTORC1 activity, and exacerbated alcoholic fatty liver, inflammation, and liver injury in mice. CONCLUSION: The dysregulation of SIRT1-DEPTOR-mTORC1 signaling is a critical determinant of ALD pathology; targeting SIRT1 and DEPTOR and selectively inhibiting mTORC1-S6K1 signaling may have therapeutic potential for treating ALD in humans. (Hepatology 2018).

The Impact of COVID-19 on Inpatient Consultations and the Role of Telehealth: A Retrospective Cohort.

Falls in non-COVID-19-related hospital admissions during the pandemic affected the reasons for dermatology consultation and mode of consultation delivery. In order to assess the impact of the pandemic and the effects of telehealth on the inpatient dermatology service, we compared consultations completed between March 17, 2020 and October 31, 2020 with the same period of 2019. Dermatology received fewer consultations for management assistance during the pandemic, possibly due to patients with chronic dermatoses not meeting admission criteria or avoiding hospitalization. Consultations were also less likely to require laboratory work, imaging, and biopsies in 2020, potentially due to frequent consultation of benign conditions enabled by telehealth and stricter enforcement of only completing the biopsies necessary for acute inpatient management. Despite the shift toward remote consultations in 2020, the impact on diagnosis and management remained unchanged compared to 2019. Providers were less likely to document clinical improvement in 2020, potentially attributable to inferior communication regarding management recommendations or an increase in diagnoses not expected to improve. While remote consultations allowed dermatologists to provide comparable care during the pandemic, further research on clinical outcomes of remote consultations is required to maximize its benefits to patients and the healthcare system. (SKINmed. 2022;20:197-204).

The Role of Inpatient Dermatology Consultations.

Inpatient dermatology has been shown to have profound effects on the care of hospitalized patients. However, dermatology consultations remain an underutilized resource. The purpose of this study was to demonstrate how dermatology affects the hospitalization of inpatients while highlighting the breadth of services provided. This cross-sectional retrospective study included all inpatient dermatology consultations completed at a large tertiary-care facility in an urban setting. It aimed to investigate the reasons for consultation, as well as the effects on diagnosis, management, disposition, and cutaneous condition by time of discharge. This study provides evidence supporting the integration of the dermatologist into the care of hospitalized patients by illuminating lesser-known areas of impact.

Penile Calciphylaxis.

A 66-year-old male presented with five days of penile pain and ulceration. The patient had a history of stage 5 chronic kidney disease and repeatedly declined hemodialysis. Wound and urine cultures were unrevealing. CT of the abdomen and pelvis did not reveal any evidence of Fournier's gangrene but identified diffuse severe calcific vasculopathy. Urology and dermatology agreed on the diagnosis of penile calciphylaxis. While diagnosis of calciphylaxis often includes histologic evidence of obstructive vasculopathy, biopsy of penile calciphylaxis is contraindicated due to increased morbidity and mortality. Management focuses wound care and correction of electrolyte abnormalities responsible for calcium deposition.

AMPK Activation by Metformin Suppresses Abnormal Extracellular Matrix Remodeling in Adipose Tissue and Ameliorates Insulin Resistance in Obesity.

Fibrosis is emerging as a hallmark of metabolically dysregulated white adipose tissue (WAT) in obesity. Although adipose tissue fibrosis impairs adipocyte plasticity, little is known about how aberrant extracellular matrix (ECM) remodeling of WAT is initiated during the development of obesity. Here we show that treatment with the antidiabetic drug metformin inhibits excessive ECM deposition in WAT of ob/ob mice and mice with diet-induced obesity, as evidenced by decreased collagen deposition surrounding adipocytes and expression of fibrotic genes including the collagen cross-linking regulator LOX Inhibition of interstitial fibrosis by metformin is likely attributable to the activation of AMPK and the suppression of transforming growth factor-ß1 (TGF-ß1)/Smad3 signaling, leading to enhanced systemic insulin sensitivity. The ability of metformin to repress TGF-ß1-induced fibrogenesis is abolished by the dominant negative AMPK in primary cells from the stromal vascular fraction. TGF-ß1-induced insulin resistance is suppressed by AMPK agonists and the constitutively active AMPK in 3T3L1 adipocytes. In omental fat depots of obese humans, interstitial fibrosis is also associated with AMPK inactivation, TGF-ß1/Smad3 induction, aberrant ECM production, myofibroblast activation, and adipocyte apoptosis. Collectively, integrated AMPK activation and TGF-ß1/Smad3 inhibition may provide a potential therapeutic approach to maintain ECM flexibility and combat chronically uncontrolled adipose tissue expansion in obesity.