scholarly journals Adult-Onset Hepatocyte GH Resistance Promotes NASH in Male Mice, Without Severe Systemic Metabolic Dysfunction

Endocrinology ◽  
2018 ◽  
Vol 159 (11) ◽  
pp. 3761-3774 ◽  
Author(s):  
Jose Cordoba-Chacon ◽  
Andre Sarmento-Cabral ◽  
Mercedes del Rio-Moreno ◽  
Alberto Diaz-Ruiz ◽  
Papasani V Subbaiah ◽  
...  
Keyword(s):  
De Novo ◽  
De Novo Lipogenesis ◽  
Metabolic Function ◽  
Metabolic Dysfunction ◽  
Adult Onset ◽  
Lipid Uptake ◽  
Nonalcoholic Fatty Liver ◽  
Adipose Tissue Lipolysis ◽  
Hepatic Markers ◽  
Inflammation Signs

Abstract Nonalcoholic fatty liver disease (NAFLD), which includes nonalcoholic steatohepatitis (NASH), is associated with reduced GH input/signaling, and GH therapy is effective in the reduction/resolution of NAFLD/NASH in selected patient populations. Our laboratory has focused on isolating the direct vs indirect effects of GH in preventing NAFLD/NASH. We reported that chow-fed, adult-onset, hepatocyte-specific, GH receptor knockdown (aHepGHRkd) mice rapidly (within 7 days) develop steatosis associated with increased hepatic de novo lipogenesis (DNL), independent of changes in systemic metabolic function. In this study, we report that 6 months after induction of aHepGHRkd early signs of NASH develop, which include hepatocyte ballooning, inflammation, signs of mild fibrosis, and elevated plasma alanine aminotransferase. These changes occur in the presence of enhanced systemic lipid utilization, without evidence of white adipose tissue lipolysis, indicating that the liver injury that develops after aHepGHRkd is due to hepatocyte-specific loss of GH signaling and not due to secondary defects in systemic metabolic function. Specifically, enhanced hepatic DNL is sustained with age in aHepGHRkd mice, associated with increased hepatic markers of lipid uptake/re-esterification. Because hepatic DNL is a hallmark of NAFLD/NASH, these studies suggest that enhancing hepatocyte GH signaling could represent an effective therapeutic target to reduce DNL and treat NASH.

scholarly journals Lipid Disorders in NAFLD and Chronic Kidney Disease

Biomedicines ◽  
2021 ◽  
Vol 9 (10) ◽  
pp. 1405
Author(s):  
Meng Yang ◽  
Chang-An Geng ◽  
Xinguang Liu ◽  
Min Guan
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Lipid Uptake ◽  
Nonalcoholic Fatty Liver ◽  
Lipid Disorders ◽  
Ectopic Lipids ◽  
Liver And Kidney ◽  
End Stage

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver dysfunction and is characterized by exaggerated lipid accumulation, inflammation and even fibrosis. It has been shown that NAFLD increases the risk of other chronic diseases, particularly chronic kidney disease (CKD). Lipid in excess could lead to liver and kidney lesions and even end-stage disease through diverse pathways. Dysregulation of lipid uptake, oxidation or de novo lipogenesis contributes to the toxic effects of ectopic lipids which promotes the development and progression of NAFLD and CKD via triggering oxidative stress, apoptosis, pro-inflammatory and profibrotic responses. Importantly, dyslipidemia and release of pro-inflammatory cytokines caused by NAFLD (specifically, nonalcoholic steatohepatitis) are considered to play important roles in the pathological progression of CKD. Growing evidence of similarities between the pathogenic mechanisms of NAFLD and those of CKD has attracted attention and urged researchers to discover their common therapeutic targets. Here, we summarize the current understanding of molecular aberrations underlying the lipid metabolism of NAFLD and CKD and clinical evidence that suggests the relevance of these pathways in humans. This review also highlights the orchestrated inter-organ cross-talk in lipid disorders, as well as therapeutic options and opportunities to counteract NAFLD and CKD.

scholarly journals Concepts and Treatment Approaches in Nonalcoholic Fatty Liver Disease

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Dina L. Halegoua-De Marzio ◽  
Jonathan M. Fenkel
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
De Novo ◽  
Imaging Techniques ◽  
De Novo Lipogenesis ◽  
Central Adiposity ◽  
Preventative Care ◽  
Nonalcoholic Fatty Liver

Nonalcoholic fatty liver disease (NAFLD) affects up to 30% of adults and is the most common liver disease in Western nations. NAFLD is associated with central adiposity, insulin resistance, type 2 diabetes mellitus, hyperlipidemia, and cardiovascular disease. It encompasses the entire spectrum of fatty liver diseases from simple steatosis to nonalcoholic steatohepatitis (NASH) with lobular/portal inflammation, hepatocellular necrosis, and fibrosis. Of those who develop NASH, 15–25% will progress to end stage liver disease and hepatocellular carcinoma over 10–20 years. Its pathogenesis is complex, and involves a state of lipid accumulation due to increased uptake of free fatty acids into the liver, impaired fatty acid beta oxidation, and increased incidence of de novo lipogenesis. Plasma aminotransferases and liver ultrasound are helpful in the diagnosis of NAFLD/NASH, but a liver biopsy is often required for definitive diagnosis. Many new plasma biomarkers and imaging techniques are now available that should improve the ability to diagnose NAFLD noninvasively Due to its complexity and extrahepatic complications, treatment of NAFLD requires a multidisciplinary approach with excellent preventative care, management, and treatment. This review will evaluate our current understanding of NAFLD, with a focus on existing therapeutic approaches and potential pharmacological developments.

scholarly journals Rho-Kinase as a Therapeutic Target for Nonalcoholic Fatty Liver Diseases

2021 ◽  
Vol 45 (5) ◽  
pp. 655-674
Author(s):  
Inês Sousa-Lima ◽  
Hyun Jeong Kim ◽  
John Jones ◽  
Young-Bum Kim
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Liver Diseases ◽  
De Novo ◽  
Rho Kinase ◽  
De Novo Lipogenesis ◽  
Major Public Health Problem ◽  
Nonalcoholic Fatty Liver ◽  
Hepatic Lipid

Nonalcoholic fatty liver disease (NAFLD) is a major public health problem and the most common form of chronic liver disease, affecting 25% of the global population. Although NAFLD is closely linked with obesity, insulin resistance, and type 2 diabetes mellitus, knowledge on its pathogenesis remains incomplete. Emerging data have underscored the importance of Rho-kinase (Rho-associated coiled-coil-containing kinase [ROCK]) action in the maintenance of normal hepatic lipid homeostasis. In particular, pharmacological blockade of ROCK in hepatocytes or hepatic stellate cells prevents the progression of liver diseases such as NAFLD and fibrosis. Moreover, mice lacking hepatic ROCK1 are protected against obesity-induced fatty liver diseases by suppressing hepatic de novo lipogenesis. Here we review the roles of ROCK as an indispensable regulator of obesity-induced fatty liver disease and highlight the key cellular pathway governing hepatic lipid accumulation, with focus on de novo lipogenesis and its impact on therapeutic potential. Consequently, a comprehensive understanding of the metabolic milieu linking to liver dysfunction triggered by ROCK activation may help identify new targets for treating fatty liver diseases such as NAFLD.

scholarly journals Phospholipid Remodeling in Physiology and Disease

2019 ◽  
Vol 81 (1) ◽  
pp. 165-188 ◽  
Author(s):  
Bo Wang ◽  
Peter Tontonoz
Keyword(s):  
Viral Infections ◽  
De Novo ◽  
Acyl Chain ◽  
Phospholipid Composition ◽  
Fatty Acyl ◽  
De Novo Lipogenesis ◽  
Lipid Absorption ◽  
Fatty Acyl Chain ◽  
Nonalcoholic Fatty Liver ◽  
Acyl Chains

Phospholipids are major constituents of biological membranes. The fatty acyl chain composition of phospholipids determines the biophysical properties of membranes and thereby affects their impact on biological processes. The composition of fatty acyl chains is also actively regulated through a deacylation and reacylation pathway called Lands’ cycle. Recent studies of mouse genetic models have demonstrated that lysophosphatidylcholine acyltransferases (LPCATs), which catalyze the incorporation of fatty acyl chains into the sn-2 site of phosphatidylcholine, play important roles in pathophysiology. Two LPCAT family members, LPCAT1 and LPCAT3, have been particularly well studied. LPCAT1 is crucial for proper lung function due to its role in pulmonary surfactant biosynthesis. LPCAT3 maintains systemic lipid homeostasis by regulating lipid absorption in intestine, lipoprotein secretion, and de novo lipogenesis in liver. Mounting evidence also suggests that changes in LPCAT activity may be potentially involved in pathological conditions, including nonalcoholic fatty liver disease, atherosclerosis, viral infections, and cancer. Pharmacological manipulation of LPCAT activity and membrane phospholipid composition may provide new therapeutic options for these conditions.

scholarly journals Losartan Prevents Hepatic Steatosis and Macrophage Polarization by Inhibiting HIF-1α in a Murine Model of NAFLD

2021 ◽  
Vol 22 (15) ◽  
pp. 7841
Author(s):  
Cheng-Hui Wang ◽  
Hsuan-Miao Liu ◽  
Zi-Yu Chang ◽  
Tse-Hung Huang ◽  
Tzung-Yan Lee
Keyword(s):  
Murine Model ◽  
Cellular Response ◽  
Lipid Droplets ◽  
De Novo ◽  
Macrophage Polarization ◽  
Hypoxia Inducible Factor ◽  
De Novo Lipogenesis ◽  
Angiotensin Ii Receptor ◽  
Nonalcoholic Fatty Liver ◽  
Associated Proteins

Hypoxia and hepatosteatosis microenvironments are fundamental traits of nonalcoholic fatty liver disease (NAFLD). Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that controls the cellular response to hypoxia and is activated in hepatocytes of patients with NAFLD, whereas the route and regulation of lipid droplets (LDs) and macrophage polarization related to systemic inflammation in NAFLD is unknown. Losartan is an angiotensin II receptor antagonist, that approved portal hypertension and related HIF-1α pathways in hepatic injury models. Here, we show that losartan in a murine model of NAFLD significantly decreased hepatic de novo lipogenesis (DNL) as well as suppressed lipid droplets (LDs), LD-associated proteins, perilipins (PLINs), and cell-death-inducing DNA-fragmentation-factor (DFF45)-like effector (CIDE) family in liver and epididymal white adipose tissues (EWAT) of ob/ob mice. Obesity-mediated macrophage M1 activation was also required for HIF-1α expression in the liver and EWAT of ob/ob mice. Administration of losartan significantly diminishes obesity-enhanced macrophage M1 activation and suppresses hepatosteatosis. Moreover, HIF-1α-mediated mitochondrial dysfunction was reversed in ob/ob mice treated with losartan. Together, the regulation of HIF-1α controls LDs protein expression and macrophage polarization, which highlights a potential target for losartan in NAFLD.

Ketogenic diet in combination with voluntary exercise impacts markers of hepatic metabolism and oxidative stress in male and female Wistar rats

2020 ◽  
Vol 45 (1) ◽  
pp. 35-44 ◽  
Author(s):  
Mary P. Moore ◽  
Rory P. Cunningham ◽  
Taylor J. Kelty ◽  
Luigi R. Boccardi ◽  
Nhu Y. Nguyen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Energy Homeostasis ◽  
De Novo ◽  
Hepatic Metabolism ◽  
De Novo Lipogenesis ◽  
Female Rats ◽  
Female Wistar Rats ◽  
Amp Activated Protein Kinase ◽  
Hepatic Markers ◽  
And Oxidative Stress

Ketogenic diets (KDs) are shown to benefit hepatic metabolism; however, their effect on the liver when combined with exercise is unknown. We investigated the effects of a KD versus a “western” diet (WD) on markers of hepatic lipid metabolism and oxidative stress in exercising rats. Male and female Wistar rats with access to voluntary running wheels were randomized to 3 groups (n = 8–14 per group): standard chow (SC; 17% fat), WD (42% fat), or KD (90.5% fat) for 7 weeks. Body fat percentage (BF%) was increased in WD and KD versus SC, although KD females displayed lower BF% versus WD (p ≤ 0.05). Liver triglycerides were higher in KD and WD versus SC but were attenuated in KD females versus WD (p ≤ 0.05). KD suppressed hepatic markers of de novo lipogenesis (fatty acid synthase, acetyl coenzyme A carboxylase) and increased markers of mitochondrial biogenesis/content (peroxisome proliferator activated receptor-1α, mitochondrial transcription factor A (TFAM), and citrate synthase activity). KD also increased hepatic glutathione peroxidase 1 and lowered oxidized glutathione. Female rats exhibited elevated hepatic markers of mitochondrial biogenesis (TFAM), mitophagy (light chain 3 II/I ratio, autophagy-related protein 12:5), and cellular energy homeostasis (phosphorylated 5′AMP-activated protein kinase/5′AMP-activated protein kinase) versus males. These data highlight that KD and exercise beneficially impacts hepatic metabolism and oxidative stress and merits further investigation. Novelty KD feeding combined with exercise improved hepatic oxidative stress, suppressed markers of de novo lipogenesis, and increased markers of mitochondrial content versus WD feeding. Males and females responded similarly to combined KD feeding and exercise. Female rats exhibited elevated hepatic markers of autophagy/mitophagy and energy homeostasis compared with male rats.

scholarly journals Increased De Novo Lipogenesis Is a Distinct Characteristic of Individuals With Nonalcoholic Fatty Liver Disease

2014 ◽  
Vol 146 (3) ◽  
pp. 726-735 ◽  
Author(s):  
Jennifer E. Lambert ◽  
Maria A. Ramos–Roman ◽  
Jeffrey D. Browning ◽  
Elizabeth J. Parks
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Nonalcoholic Fatty Liver

scholarly journals Association between Nicotinamide Phosphoribosyltransferase and de novo Lipogenesis in Nonalcoholic Fatty Liver Disease

2017 ◽  
Vol 26 (3) ◽  
pp. 251-257 ◽  
Author(s):  
Bahareh Amirkalali ◽  
Masoud Reza Sohrabi ◽  
Ali Esrafily ◽  
Mahmoud Jalali ◽  
Ali Gholami ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Nicotinamide Phosphoribosyltransferase ◽  
Nonalcoholic Fatty Liver

scholarly journals Combining metformin therapy with caloric restriction for the management of type 2 diabetes and nonalcoholic fatty liver disease in obese rats

2015 ◽  
Vol 40 (10) ◽  
pp. 1038-1047 ◽  
Author(s):  
Melissa A. Linden ◽  
Kristi T. Lopez ◽  
Justin A. Fletcher ◽  
E. Matthew Morris ◽  
Grace M. Meers ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Weight Loss ◽  
Liver Disease ◽  
Caloric Restriction ◽  
Fatty Liver Disease ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Nonalcoholic Fatty Liver ◽  
Oletf Rats

Weight loss is recommended for patients with nonalcoholic fatty liver disease (NAFLD), while metformin may lower liver enzymes in type 2 diabetics. Yet, the efficacy of the combination of weight loss and metformin in the treatment of NAFLD is unclear. We assessed the effects of metformin, caloric restriction, and their combination on NAFLD in diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Male OLETF rats (age 20 weeks; n = 6–8 per group) were fed ad libitum (AL), given metformin (300 mg·kg−1·day−1; Met), calorically restricted (70% of AL; CR), or calorically restricted and given metformin (CR+Met) for 12 weeks. Met lowered adiposity compared with AL but not to the same magnitude as CR or CR+Met (p < 0.05). Although only CR improved fasting insulin and glucose, the combination of CR+Met was needed to improve post-challenge glucose tolerance. All treatments lowered hepatic triglycerides, but further improvements were observed in the CR groups (p < 0.05, Met vs. CR or CR+Met) and a further reduction in serum alanine aminotransferases was observed in CR+Met rats. CR lowered markers of hepatic de novo lipogenesis (fatty acid synthase, acetyl-CoA carboxylase (ACC), and stearoyl-CoA desaturase-1 (SCD-1)) and increased hepatic mitochondrial activity (palmitate oxidation and β-hydroxyacyl CoA dehydrogenase (β-HAD) activity). Changes were enhanced in the CR+Met group for ACC, SCD-1, β-HAD, and the mitophagy marker BNIP3. Met decreased total hepatic mTOR content and inhibited mTOR complex 1, which may have contributed to Met-induced reductions in de novo lipogenesis. These findings in the OLETF rat suggest that the combination of caloric restriction and metformin may provide a more optimal approach than either treatment alone in the management of type 2 diabetes and NAFLD.

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