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Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and is strongly associated with obesity-related ectopic fat accumulation in the liver. Hepatic lipid accumulation encompasses a histological spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), which can progress to cirrhosis and hepatocellular carcinoma. Given that dysregulated hepatic lipid metabolism may be an onset factor in NAFLD, understanding how hepatic lipid metabolism is modulated in healthy subjects and which steps are dysregulated in NAFLD subjects is crucial to identify effective therapeutic targets. Additionally, hepatic inflammation is involved in chronic hepatocyte damage during NAFLD progression. As a key immune signaling hub that mediates NF-κB activation, the IκB kinase (IKK) complex, including IKKα, IKKβ, and IKKγ (NEMO), has been studied as a crucial regulator of the hepatic inflammatory response and hepatocyte survival. Notably, TANK-binding kinase 1 (TBK1), an IKK-related kinase, has recently been revealed as a potential link between hepatic inflammation and energy metabolism. Here, we review (1) the biochemical steps of hepatic lipid metabolism; (2) dysregulated lipid metabolism in obesity and NAFLD; and (3) the roles of IKKs and TBK1 in obesity and NAFLD.

Macrophage proinflammatory activation is an important etiologic component of the development of insulin resistance and metabolic dysfunction in obesity. However, the underlying mechanisms are not clearly understood. Here, we demonstrate that a mitochondrial inner membrane protein, adenine nucleotide translocase 2 (ANT2), mediates proinflammatory activation of adipose tissue macrophages (ATMs) in obesity. Ant2 expression was increased in ATMs of obese mice compared with lean mice. Myeloid-specific ANT2-knockout (ANT2-MKO) mice showed decreased adipose tissue inflammation and improved insulin sensitivity and glucose tolerance in HFD/obesity. At the molecular level, we found that ANT2 mediates free fatty acid-induced mitochondrial permeability transition, leading to increased mitochondrial reactive oxygen species production and damage. In turn, this increased HIF-1α expression and NF-κB activation, leading to proinflammatory macrophage activation. Our results provide a previously unknown mechanism for how obesity induces proinflammatory activation of macrophages with propagation of low-grade chronic inflammation (metaflammation).

Hepatic TANK (TRAF family member associated NFκB activator)-binding kinase 1 (TBK1) activity is increased during obesity, and administration of a TBK1 inhibitor reduces fatty liver. Surprisingly, liver-specific TBK1 knockout in mice produces fatty liver by reducing fatty acid oxidation. TBK1 functions as a scaffolding protein to localize acyl-CoA synthetase long-chain family member 1 (ACSL1) to mitochondria, which generates acyl-CoAs that are channeled for β-oxidation. TBK1 is induced during fasting and maintained in the unphosphorylated, inactive state, enabling its high affinity binding to ACSL1 in mitochondria. In TBK1-deficient liver, ACSL1 is shifted to the endoplasmic reticulum to promote fatty acid re-esterification in lieu of oxidation in response to fasting, which accelerates hepatic lipid accumulation. The impaired fatty acid oxidation in TBK1-deficient hepatocytes is rescued by the expression of kinase-dead TBK1. Thus, TBK1 operates as a rheostat to direct the fate of fatty acids in hepatocytes, supporting oxidation when inactive during fasting and promoting re-esterification when activated during obesity.

Decreased adipose tissue oxygen tension and increased HIF-1α expression can trigger adipose tissue inflammation and dysfunction in obesity. Our current understanding of obesity-associated decreased adipose tissue oxygen tension is mainly focused on changes in oxygen supply and angiogenesis. Here, we demonstrate that increased adipocyte O2 demand, mediated by ANT2 activity, is the dominant cause of adipocyte hypoxia. Deletion of adipocyte Ant2 improves obesity-induced intracellular adipocyte hypoxia by decreasing obesity-induced adipocyte oxygen demand, without effects on mitochondrial number or mass, or oligomycin-sensitive respiration. This led to decreased adipose tissue HIF-1α expression and inflammation with improved glucose tolerance and insulin resistance in both a preventative or therapeutic setting. Our results suggest that ANT2 may be a target for the development of insulin sensitizing drugs and that ANT2 inhibition might have clinical utility.

Despite significant strides in big data technology, extracting information from unstructured clinical data remains a formidable challenge. This study investigated the utility of large language models (LLMs) for extracting clinical data from unstructured radiological reports without additional training. In this retrospective study, 1800 radiologic reports, 600 from each of the three university hospitals, were collected, with seven pulmonary outcomes defined. Three pulmonology-trained specialists discerned the presence or absence of diseases. Data extraction from the reports was executed using Google Gemini Pro 1.0, OpenAI's GPT-3.5, and GPT-4. The gold standard was predicated on agreement between at least two pulmonologists. This study evaluated the performance of the three LLMs in diagnosing seven pulmonary diseases (active tuberculosis, emphysema, interstitial lung disease, lung cancer, pleural effusion, pneumonia, and pulmonary edema) utilizing chest radiography and computed tomography scans. All models exhibited high accuracy (0.85–1.00) for most conditions. GPT-4 consistently outperformed its counterparts, demonstrating a sensitivity of 0.71–1.00; specificity of 0.89–1.00; and accuracy of 0.89 and 0.99 across both modalities, thus underscoring its superior capability in interpreting radiological reports. Notably, the accuracy of pleural effusion and emphysema on chest radiographs and pulmonary edema on chest computed tomography scans reached 0.99. The proficiency of LLMs, particularly GPT-4, in accurately classifying unstructured radiological data hints at their potential as alternatives to the traditional manual chart reviews conducted by clinicians. [ABSTRACT FROM AUTHOR]

Stellera chamaejasme L. (SCL) is a perennial herb with demonstrated bioactivities against inflammation and metabolic dysfunction. Adipocyte differentiation is a critical regulator of metabolic homeostasis and a promising target for the treatment of metabolic diseases, so we examined the effects of SCL on adipogenesis. A methanol extract of SCL dose-dependently suppressed intracellular lipid accumulation in adipocyte precursors cultured under differentiation induction conditions and reduced expression of the adipogenic transcription factors PPARγ and C/EBPα as well as the downstream lipogenic genes fatty acid binding protein 4, adiponectin, fatty acid synthase, and stearoyl-CoA desaturase. The extract also promoted precursor cell proliferation and altered expression of the cell cycle regulators cyclin-dependent kinase 4, cyclin E, and cyclin D1. In addition, SCL extract stimulated extracellular signal-regulated kinase (ERK) phosphorylation, while pharmacological inhibition of ERK effectively blocked the inhibitory effects of SCL extract on preadipocyte differentiation. These results suggest that SCL extract contains bioactive compounds that can suppress adipogenesis through modulation of the ERK pathway. [ABSTRACT FROM AUTHOR]

Particulate matter (PM) is a major air pollutant that has led to global health concerns and can cause and exacerbate chronic obstructive pulmonary disease (COPD). We asked patients with COPD to complete a detailed questionnaire about their lifestyle practices to reduce PM2.5 exposure and analyzed the relationship between ambient PM2.5 concentrations and lifestyle practices. We prospectively enrolled 104 COPD patients from four hospitals in different areas of Korea. They completed detailed questionnaires twice (at enrollment and the end of the study) and Internet of Things-based sensors were installed in their homes to continuously measure PM2.5 for 1 year. The relationship between PM2.5 concentrations, lifestyle practices, and COPD exacerbations were analyzed in each season. The PM2.5 concentration was higher outdoors than indoors in all seasons except summer, and the difference was largest in winter. The six lifestyle practices that significantly lowered the annual indoor PM2.5 concentration compared with the outdoors. The higher the economic status and educational level of patients, the lower the indoor PM2.5 concentration. Some lifestyle practices were associated with reduced small airway resistance, presented as R5–R20 determined by impulse oscillometry, and scores of the St. George's Respiratory Questionnaire. Some lifestyle practices are associated with reduced indoor PM2.5 concentrations and can even affect clinical outcomes, including small airway resistance and quality of life of COPD patients. [ABSTRACT FROM AUTHOR]