Hepatic fibrosis: Targeting peroxisome proliferator-activated receptor alpha from mechanism to medicines.

Liver fibrosis is the result of sustained chronic liver injury and inflammation leading to hepatocyte cell death followed by the formation of fibrous scars, which is the hallmark of NASH and alcoholic steatohepatitis and can lead to cirrhosis, HCC, and liver failure. Although progress has been made in understanding the pathogenesis and clinical consequences of hepatic fibrosis, therapeutic strategies for this disease are limited. Preclinical studies suggest that peroxisome proliferator-activated receptor alpha plays an important role in preventing the development of liver fibrosis by activating genes involved in detoxifying lipotoxicity and toxins, transrepressing genes involved in inflammation, and inhibiting activation of hepatic stellate cells. Given the robust preclinical data, several peroxisome proliferator-activated receptor alpha agonists have been tested in clinical trials for liver fibrosis. Here, we provide an update on recent progress in understanding the mechanisms by which peroxisome proliferator-activated receptor alpha prevents fibrosis and discuss the potential of targeting PPARα for the development of antifibrotic treatments.

Intermittent fasting shifts the diurnal transcriptome atlas of transcription factors.

Intermittent fasting remains a safe and effective strategy to ameliorate various age-related diseases, but its specific mechanisms are not fully understood. Considering that transcription factors (TFs) determine the response to environmental signals, here, we profiled the diurnal expression of 600 samples across four metabolic tissues sampled every 4 over 24 h from mice placed on five different feeding regimens to provide an atlas of TFs in biological space, time, and feeding regimen. Results showed that 1218 TFs exhibited tissue-specific and temporal expression profiles in ad libitum mice, of which 974 displayed significant oscillations at least in one tissue. Intermittent fasting triggered more than 90% (1161 in 1234) of TFs to oscillate somewhere in the body and repartitioned their tissue-specific expression. A single round of fasting generally promoted TF expression, especially in skeletal muscle and adipose tissues, while intermittent fasting mainly suppressed TF expression. Intermittent fasting down-regulated aging pathway and upregulated the pathway responsible for the inhibition of mammalian target of rapamycin (mTOR). Intermittent fasting shifts the diurnal transcriptome atlas of TFs, and mTOR inhibition may orchestrate intermittent fasting-induced health improvements. This atlas offers a reference and resource to understand how TFs and intermittent fasting may contribute to diurnal rhythm oscillation and bring about specific health benefits.

Construction of a Cu2+-Responsive NIR Fluorescent Probe and the Preliminary Evaluation of its Multifunctional Application.

Cu2+ was deemed as toxic and the most common heavy metal pollution in the water and food. Meanwhile, endogenous Cu2+ was deeply involved in plenty of physiological and pathological processes of human. Cu2+ imbalance was related to multiple diseases. Here we developed a Cu2+-responsive NIR probe HX, which not only demonstrated obvious color change when subjected to Cu2+, but also showed linear-dependent NIR fluorescence emission to Cu2+ concentration for Cu2+ detection and quantification both in vitro and in vivo. When HX was applied to imaging Cu2+ in the cell or living animals, intracellular Cu2+ fluctuation and Cu2+ accumulation in the liver could be visualized to indicate the copper level in the cell or organs with low background signals. Meanwhile, by applying HX to monitor Cu2+ uptake in the tumor, copper transporter function could be evaluated to screen the patient who are sensitivity to platinum drug.

Sertraline Promotes Health and Longevity in Caenorhabditis elegans.

INTRODUCTION: While several antidepressants have been identified as potential geroprotectors, the effect and mechanism of sertraline on healthspan remain to be elucidated. Here, we explored the role of sertraline in the lifespan and healthspan of Caenorhabditis elegans. METHODS: The optimal effect concentration of sertraline was first screened in wild-type N2 worms under heat stress conditions. Then, we examined the effects of sertraline on lifespan, reproduction, lipofuscin accumulation, mobility, and stress resistance. Finally, the expression of serotonin signaling and aging-related genes was investigated to explore the underlying mechanism, and the lifespan assays were performed in ser-7 RNAi strain, daf-2, daf-16, and aak-2 mutants. RESULTS: Sertraline extended the lifespan in C. elegans with concomitant extension of healthspan as indicated by increasing mobility and reducing fertility and lipofuscin accumulation, as well as enhanced resistance to different abiotic stresses. Mechanistically, ser-7 orchestrated sertraline-induced longevity via the regulation of insulin and AMPK pathways, and sertraline-induced lifespan extension in nematodes was abolished in ser-7 RNAi strain, daf-2, daf-16, and aak-2 mutants. CONCLUSION: Sertraline promotes health and longevity in C. elegans through ser-7-insulin/AMPK pathways.

Extensive involvement of indolent T-cell lymphoma in a patient with ulcerative colitis.

Indolent T-cell lymphoma is a rare disease. Here we presented a 53-year-old male patient initially diagnosed as ulcerative colitis in 2000 that finally developed into extensive indolent T-cell lymphoma in 2022. We also described the differences between indolent T-cell lymphoma and inflammatory bowel disease, and the possible disease progression into lymphoma after biological therapy.

Advances in Traditional Chinese Medicine research in diabetic kidney disease treatment.

CONTEXT: Diabetic kidney disease (DKD) is a prominent complication arising from diabetic microangiopathy, and its prevalence and renal impact have placed it as the primary cause of end-stage renal disease. Traditional Chinese Medicine (TCM) has the distinct advantage of multifaceted and multilevel therapeutic attributes that show efficacy in improving clinical symptoms, reducing proteinuria, protecting renal function, and slowing DKD progression. Over recent decades, extensive research has explored the mechanisms of TCM for preventing and managing DKD, with substantial studies that endorse the therapeutic benefits of TCM compounds and single agents in the medical intervention of DKD. OBJECTIVE: This review lays the foundation for future evidence-based research efforts and provide a reference point for DKD investigation. METHODS: The relevant literature published in Chinese and English up to 30 June 2023, was sourced from PubMed, Cochrane Library, VIP Database for Chinese Technical Periodicals (VIP), Wanfang Data, CNKI, and China Biology Medicine disc (CBM). The process involved examining and summarizing research on TCM laboratory tests and clinical randomized controlled trials for DKD treatment. RESULTS AND CONCLUSIONS: The TCM intervention has shown the potential to inhibit the expression of inflammatory cytokines and various growth factors, lower blood glucose levels, and significantly affect insulin resistance, lipid metabolism, and improved renal function. Furthermore, the efficacy of TCM can be optimized by tailoring personalized treatment regimens based on the unique profiles of individual patients. We anticipate further rigorous and comprehensive clinical and foundational investigations into the mechanisms underlying the role of TCM in treating DKD.

1-D and 2-D Direction of Arrival Estimation in a Conical Conformal Array: Design and Implementation.

Direction of arrival (DOA) estimation for conformal arrays is challenging due to non-omnidirectional element patterns and shadow effects. Conical conformal array (CCA) can avoid the shadow effect at small elevation angles. So CCA is suitable for DOA estimation on both azimuth and elevation angles at small elevation angles. However, the element pattern in CCA cannot be obtained by conventional directional element coordinate transformation. Its local element pattern also has connection with the cone angle. The paper establishes the CCA radiation pattern in local coordinate system using 2-D coordinate transformation. In addition, in the case of large elevation angle, only half elements of the CCA can receive signal due to the shadow effect. The array degrees of freedom (DOF) are reduced by halves. We introduce the difference coarray method, which increases the DOF. Moreover, we propose a more accurate propagator method for 2-D cases. This method constructs a new propagation matrix and reduces the estimation error. In addition, this method reduces computational complexity by using linear computations instead of eigenvalue decomposition (EVD) and avoids spectral search. Simulation and experiment verify the estimation performance of the CCA. Both demonstrate the CCA model established in this paper is corresponding to the designed CCA antenna, and the proposed algorithms meet the needs of CCA angle detection. When the number of array elements is 12, the estimation accuracy is about 5 degrees.

Mitochondria-Targeted Fluorescent Nanoparticles with Large Stokes Shift for Long-Term BioImaging.

Mitochondria (MITO) play a significant role in various physiological processes and are a key organelle associated with different human diseases including cancer, diabetes mellitus, atherosclerosis, Alzheimer's disease, etc. Thus, detecting the activity of MITO in real time is becoming more and more important. Herein, a novel class of amphiphilic aggregation-induced emission (AIE) active probe fluorescence (AC-QC nanoparticles) based on a quinoxalinone scaffold was developed for imaging MITO. AC-QC nanoparticles possess an excellent ability to monitor MITO in real-time. This probe demonstrated the following advantages: (1) lower cytotoxicity; (2) superior photostability; and (3) good performance in long-term imaging in vitro. Each result of these indicates that self-assembled AC-QC nanoparticles can be used as effective and promising MITO-targeted fluorescent probes.

circFARP1 enables cancer-associated fibroblasts to promote gemcitabine resistance in pancreatic cancer via the LIF/STAT3 axis.

BACKGROUND: Cancer-associated fibroblasts (CAFs) are critically involved in gemcitabine (GEM) resistance in pancreatic ductal adenocarcinoma (PDAC). However, the underlying mechanism by which CAFs promote chemotherapy resistance remains unexplored. Here, we explored the role of circRNAs in CAF-induced GEM resistance in PDAC. METHODS: circRNA sequencing and quantitative real-time PCR (qRT-PCR) were utilized to screen CAF-specific circRNAs. The effects of CAF circFARP1 expression on GEM resistance in tumor cells were assessed in vitro and in vivo. RNA-seq, RNA pulldown, RNA immunoprecipitation, and luciferase reporter assays were used to screen the downstream target and underlying mechanism of circFARP1. RESULTS: circFARP1 (hsa_circ_0002557), a CAF-specific circRNA, was positively correlated with GEM chemoresistance and poor survival in an advanced PDAC cohort. Silencing or overexpressing circFARP1 in CAFs altered the ability of CAFs to induce tumor cell stemness and GEM resistance via leukemia inhibitory factor (LIF). Mechanistically, we found that circFARP1 directly binds with caveolin 1 (CAV1) and blocks the interaction of CAV1 and the E3 ubiquitin-protein ligase zinc and ring finger 1 (ZNRF1) to inhibit CAV1 degradation, which enhances LIF secretion. In addition, circFARP1 upregulated LIF expression by sponging miR-660-3p. Moreover, high circFARP1 levels were positively correlated with elevated serum LIF levels in PDAC and poor patient survival. Decreasing circFARP1 levels and neutralizing LIF significantly suppressed PDAC growth and GEM resistance in patient-derived xenograft models. CONCLUSIONS: The circFARP1/CAV1/miR-660-3p/LIF axis is critical for CAF-induced GEM resistance in PDAC. Hence, circFARP1 may be a potential therapeutic target for PDAC.

Pathogenesis, multi-omics research, and clinical treatment of psoriasis.

Psoriasis is a common inflammatory skin disease involving interactions between keratinocytes and immune cells that significantly affects the quality of life. It is characterized by hyperproliferation and abnormal differentiation of keratinocytes and excessive infiltration of immune cells in the dermis and epidermis. The immune mechanism underlying this disease has been elucidated in the past few years. Research shows that psoriasis is regulated by the complex interactions among immune cells, such as keratinocytes, dendritic cells, T lymphocytes, neutrophils, macrophages, natural killer cells, mast cells, and other immune cells. An increasing number of signaling pathways have been found to be involved in the pathogenesis of psoriasis, which has prompted the search for new treatment targets. In the past decades, studies on the pathogenesis of psoriasis have focused on the development of targeted and highly effective therapies. In this review, we have discussed the relationship between various types of immune cells and psoriasis and summarized the major signaling pathways involved in the pathogenesis of psoriasis, including the PI3K/AKT/mTOR, JAK-STAT, JNK, and WNT pathways. In addition, we have discussed the results of the latest omics research on psoriasis and the epigenetics of the disease, which provide insights regarding its pathogenesis and therapeutic prospects; we have also summarized its treatment strategies and observations of clinical trials. In this paper, the various aspects of psoriasis are described in detail, and the limitations of the current treatment methods are emphasized. It is necessary to improve and innovate treatment methods from the molecular level of pathogenesis, and further provide new ideas for the treatment and research of psoriasis.

Direction of plant-soil feedback determines plant responses to drought.

Droughts exarcerbate Plant-soil feedbacks (PSFs) making positive PSFs more positive and negative PSFs more negative. Alterations in PSFs that droughts induce could relate to the rooting depth of the tested plants. We present some rare evidence on how a driver of global change will alter a biotic interaction.

Practice Patterns and Perioperative Outcomes of Laparoscopic Pancreaticoduodenectomy in China: A Retrospective Multicenter Analysis of 1029 Patients.

OBJECTIVE: The aim of the study was to analyze the outcomes of patients who have undergone laparoscopic pancreaticoduodenectomy (LPD) in China. SUMMARY BACKGROUND DATA: LPD is being increasingly used worldwide, but an extensive, detailed, systematic, multicenter analysis of the procedure has not been performed. METHODS: We retrospectively reviewed 1029 consecutive patients who had undergone LPD between January 2010 and August 2016 in China. Univariate and multivariate analyses of patient demographics, changes in outcome over time, technical learning curves, and the relationship between hospital or surgeon volume and patient outcomes were performed. RESULTS: Among the 1029 patients, 61 (5.93%) required conversion to laparotomy. The median operation time (OT) was 441.34 minutes, and the major complications occurred in 511 patients (49.66%). There were 21 deaths (2.43%) within 30 days, and a total of 61 (5.93%) within 90 days. Discounting the effects of the early learning phase, critical parameters improved significantly with surgeons' experience with the procedure. Univariate and multivariate analyses revealed that the pancreatic anastomosis technique, preoperative biliary drainage method, and total bilirubin were linked to several outcome measures, including OT, estimated intraoperative blood loss, and mortality. Multicenter analyses of the learning curve revealed 3 phases, with proficiency thresholds at 40 and 104 cases. Higher hospital, department, and surgeon volume, as well as surgeon experience with minimally invasive surgery, were associated with a lower risk of surgical failure. CONCLUSIONS: LPD is technically safe and feasible, with acceptable rates of morbidity and mortality. Nonetheless, long learning curves, low-volume hospitals, and surgical inexperience are associated with higher rates of complications and mortality.

A Robust and Fast Method for Sidescan Sonar Image Segmentation Based on Region Growing.

For high-resolution side scan sonar images, accurate and fast segmentation of sonar images is crucial for underwater target detection and recognition. However, due to the characteristics of low signal-to-noise ratio (SNR) and complex environmental noise of sonar, the existing methods with high accuracy and good robustness are mostly iterative methods with high complexity and poor real-time performance. For this purpose, a region growing based segmentation using the likelihood ratio testing method (RGLT) is proposed. This method obtains the seed points in the highlight and the shadow regions by likelihood ratio testing based on the statistical probability distribution and then grows them according to the similarity criterion. The growth avoids the processing of the seabed reverberation regions, which account for the largest proportion of sonar images, thus greatly reducing segmentation time and improving segmentation accuracy. In addition, a pre-processing filtering method called standard deviation filtering (STDF) is proposed to improve the SNR and remove the speckle noise. Experiments were conducted on three sonar databases, which showed that RGLT has significantly improved quantitative metrics such as accuracy, speed, and segmentation visual effects. The average accuracy and running times of the proposed segmentation method for 100 × 400 images are separately 95.90% and 0.44 s.

Distribution Characteristics of Ground Echo Amplitude and Recognition of Signal Grazing Angle.

With the continuous advancement of electronic technology, terahertz technology has gradually been applied on radar. Since short wavelength causes severe ground clutter, this paper studies the amplitude distribution statistical characteristics of the terahertz radar clutter based on the measured data, and provides technical support for the radar clutter suppression. Clutter distribution is the function of the radar glancing angle. In order to achieve targeted suppression, in this paper, selected axial integral bispectrum (selected AIB) feature is selected as deep belief network (DBN)input to complete the radar glancing angle recognition and the network structure, network training method, robustness are analyzed also. The ground clutter amplitude distribution can follow normal distribution at 0~45° grazing angles. The Weibull distribution and G0 distribution can describe the amplitude probability density function of ground clutter at grazing angles 85° and 65°. The recognition rate of different signal grazing angles can reach 91% on three different terrains. At the same time, the wide applicability of the selected AIB feature is verified. The analysis results of ground clutter amplitude characteristics play an important role in the suppression of radar ground clutter.

3D DCT Based Image Compression Method for the Medical Endoscopic Application.

This paper proposes a novel 3D discrete cosine transform (DCT) based image compression method for medical endoscopic applications. Due to the high correlation among color components of wireless capsule endoscopy (WCE) images, the original 2D Bayer data pattern is reconstructed into a new 3D data pattern, and 3D DCT is adopted to compress the 3D data for high compression ratio and high quality. For the low computational complexity of 3D-DCT, an optimized 4-point DCT butterfly structure without multiplication operation is proposed. Due to the unique characteristics of the 3D data pattern, the quantization and zigzag scan are ameliorated. To further improve the visual quality of decompressed images, a frequency-domain filter is proposed to eliminate the blocking artifacts adaptively. Experiments show that our method attains an average compression ratio (CR) of 22.94:1 with the peak signal to noise ratio (PSNR) of 40.73 dB, which outperforms state-of-the-art methods.

Angiopoietin-2 induces angiogenesis via exosomes in human hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is a highly vascularized solid tumor. Angiopoietin-2 (ANGPT2) has been described as an attractive target for antiangiogenic therapy. Exosomes are small extracellular vesicles secreted by most cell types and contribute to cell-to-cell communication by delivering functional cargo to recipient cells. The expression of ANGPT2 in tumor-derived exosomes remains unknown. METHODS: We detected the ANGPT2 expression in HCC-derived exosomes by immunoblotting, enzyme-linked immunosorbent assay and immunogold labeling, then observed exosomal ANGPT2 internalization and recycling by confocal laser scanning microscopy, co-immunoprecipitation and immunoblotting. We used two HCC cell lines (Hep3B and MHCC97H) to overexpress ANGPT2 by lentivirus infection or knockdown ANGPT2 by the CRISPR/Cas system, then isolated exosomes to coculture with human umbilical vein endothelial cells (HUVECs) and observed the angiogenesis by Matrigel microtubule formation assay, transwell migration assay, wound healing assay, cell counting kit-8 assay, immunoblotting and in vivo tumorigenesis assay. RESULTS: We found that HCC-derived exosomes carried ANGPT2 and delivered it into HUVECs by exosome endocytosis, this delivery led to a notable increase in angiogenesis by a Tie2-independent pathway. Concomitantly, we observed that HCC cell-secreted exosomal ANGPT2 was recycled by recipient HUVECs and might be reused. In addition, the CRISPR-Cas systems to knock down ANGPT2 significantly inhibited the angiogenesis induced by HCC cell-secreted exosomal ANGPT2, and obviously suppressed the epithelial-mesenchymal transition activation in HCC. CONCLUSIONS: Taken together, these results reveal a novel pathway of tumor angiogenesis induced by HCC cell-secreted exosomal ANGPT2 that is different from the classic ANGPT2/Tie2 pathway. This way may be a potential therapeutic target for antiangiogenic therapy. Video Abstract.

Preoperative Diagnosis of Regional Lymph Node Metastasis of Colorectal Cancer With Quantitative Parameters From Dual-Energy CT.

OBJECTIVE. The purpose of this study was to investigate the performance of quantitative parameters derived from dual-energy CT (DECT) in the preoperative diagnosis of regional metastatic lymph nodes (LNs) in patients with colorectal cancer. SUBJECTS AND METHODS. Triphasic contrast-enhanced DECT was performed for 178 patients with colon or high rectal cancer. The morphologic criteria, short-axis diameter, and quantitative DECT parameters of the largest regional LN were measured and compared between pathologically metastatic and nonmetastatic LNs. Univariate and multivariable logistic regression analyses were used to determine the independent DECT parameters for predicting LN metastasis. Diagnostic performance measures were assessed by ROC curve analysis and compared by McNemar test. RESULTS. A total of 178 largest LNs (72 metastatic, 106 nonmetastatic) were identified in 178 patients. The best single DECT parameter for differentiation between metastatic and nonmetastatic LNs was normalized effective atomic number (Zeff) in the portal venous phase (AUC, 0.871; accuracy, 84.8%). These values were higher than those of morphologic criteria (AUC, 0.505-0.624; accuracy, 47.8-62.4%) and short-axis diameter (AUC, 0.647; accuracy, 66.3%) (p < 0.05). The diagnostic accuracy of combined normalized iodine concentration in the arterial phase and normalized effective atomic number in the portal venous phase was further improved to 87.1% (AUC, 0.916). CONCLUSION. Quantitative parameters derived from DECT can be used to improve preoperative diagnostic accuracy in evaluation for regional metastatic LNs in patients with colorectal cancer.

Laparoscopic duodenum-preserving total pancreatic head resection: a novel surgical approach for benign or low-grade malignant tumors.

BACKGROUND: Duodenum-preserving total pancreatic head resection (DPPHRt) is an accepted alternative surgical procedure for benign or low-grade malignant tumors of the pancreatic head by preserving the duodenum with its intact blood supply from the pancreatic duodenal arterial arcade. This study describes our experience in laparoscopic DPPHRt (LDPPHRt). To our knowledge, this is the first description of this novel minimally invasive operation. METHODS: From August 2016 to May 2017, all consecutive patients who underwent LDPPHRt for pancreatic head lesions at the HPB Surgery Department, Sun Yat-Sen Memorial Hospital in Guangzhou, China were enrolled into this retrospective study. RESULTS: There were ten women and two men. The average age was 37.3 years (range 8-61 years). The average diameter of the pancreatic head lesions on pre-operative CT/MR was 3.7 cm (range 2-4.8 cm). All the LDPPHRt procedures were performed successfully. There was no peri-operative death. The average operative time was 272.5 min (range 210-320 min). The average blood loss was 215 ml (range 50-450 ml). Post-operative complications included pancreatic fistula grade B (two patients, or 16.7%) and biliary fistula (two patients, or 16.7%). All the complications responded well to conservative treatment. The mean post-operative hospital stay was 11.5 days (range 6-25 days). CONCLUSIONS: LDPPHRt provided a minimally invasive approach with good organ-preservation for benign or low-grade malignant tumors of the pancreatic head. The long-term oncological outcomes, and the exocrine and endocrine pancreatic functions after this operation require further studies.

An Improved Two-Dimensional Direction-Of-Arrival Estimation Algorithm for L-Shaped Nested Arrays with Small Sample Sizes.

In this paper, an improved two-dimensional (2-D) direction of arrival (DOA) estimation algorithm for L-shaped nested arrays is proposed. Unlike the approach for a classical nested array, which use the auto-correlation matrix (ACM) to increase the degrees of freedom (DOF), we utilize the cross-correlation matrix (CCM) of different sub-arrays to generate two long consecutive virtual arrays. These acquire a large number of DOF without redundant elements and eliminate noise effects. Furthermore, we reconstruct the CCM based on the singular value decomposition (SVD) operation in order to reduce the perturbation of noise for small numbers of samples. To cope with the matrix rank deficiency of the virtual arrays, we construct the full rank equivalent covariance matrices by using the output and its conjugate vector of virtual arrays. The unitary estimation of signal parameters via rotational invariance technique (ESPRIT) is then performed on the covariance matrices to obtain the DOA of incident signals with low computational complexity. Finally, angle pairing is achieved by deriving the equivalent signal vector of the virtual arrays using the estimated angles. Numerical simulation results show that the proposed algorithm not only provides more accurate 2-D DOA estimation performance with low complexity, but also achieves angle estimation for small numbers of samples compared to existing similar methods.

Extrahepatic PPARα modulates fatty acid oxidation and attenuates fasting-induced hepatosteatosis in mice.

PPARα (PPARA), expressed in most oxidative tissues, is a major regulator of lipid homeostasis; hepatic PPARA plays a critical role during the adaptive fasting response by promoting FA oxidation (FAO). To clarify whether extrahepatic PPARA activity can protect against lipid overload when hepatic PPARA is impaired, lipid accumulation was compared in WT (Ppara+/+), total body Ppara-null (Ppara-/-), and hepatocyte-specific Ppara-null (PparaΔHep) mice that were fasted for 24 h. Histologic staining indicated reduced lipid accumulation in PparaΔHep versus Ppara-/- mice, and biochemical analyses revealed diminished medium- and long-chain FA accumulation in PparaΔHep mouse livers. Hepatic PPARA target genes were suppressed in both mouse models. Serum FFAs increased in all genotypes after fasting but were highest in Ppara-/- mice. In PparaΔHep mice, FAO genes were increased in brown adipose tissue, heart, and muscle, and total lipase activity was elevated in the muscle and heart, suggesting increased lipid utilization. Thus, extrahepatic PPARA activity reduces systemic lipid load when hepatic lipid metabolism is impaired by elevating FAO and lipase activity in other tissues and, as a result, protects against fasting-induced hepatosteatosis. This has important clinical implications in disease states with impaired hepatic PPARA function, such as nonalcoholic steatohepatitis and nonalcoholic fatty liver disease.