Free fatty acids repress small heterodimer partner (SHP) activation and adiponectin counteracts bile acid-induced liver injury in superobese patients with nonalcoholic steatohepatitis

The heteromeric steroid transporter organic solute transporter α/β (OSTα/β, SLC51A/B) was discovered over a decade ago, but its physiological significance in the liver remains uncertain. A major challenge has been the lack of suitable models expressing OSTα/β. Based on observations first reported here that hepatic OSTα/β is upregulated in nonalcoholic steatohepatitis, the aim of this research was to develop an in vitro model to evaluate OSTα/β function and interaction with drugs and bile acids. OSTα/β expression in human liver tissue was analyzed by quantitative RT-PCR, Western blotting, and immunofluorescence. Radiolabeled compounds were used to determine OSTα/β-mediated transport in the established in vitro model. The effect of bile acids and drugs, including those associated with cholestatic drug-induced liver injury, on OSTα/β-mediated transport was evaluated. Expression of OSTα/β was elevated in the liver of patients with nonalcoholic steatohepatitis and primary biliary cholangitis, whereas hepatocyte expression of OSTα/β was low in control liver tissue. Studies in the novel cell-based system showed rapid and linear OSTα/β-mediated transport for all tested compounds: dehydroepiandrosterone sulfate, digoxin, estrone sulfate, and taurocholate. The interaction study with 26 compounds revealed novel OSTα/β inhibitors: a biomarker for cholestasis, glycochenodeoxycholic acid; the major metabolite of troglitazone, troglitazone sulfate; and a macrocyclic antibiotic, fidaxomicin. Additionally, some drugs (e.g., digoxin) consistently stimulated taurocholate uptake in OSTα/β-overexpressing cells. Our findings demonstrate that OSTα/β is an important transporter in liver disease and imply a role for this transporter in bile acid-bile acid and drug-bile acid interactions, as well as cholestatic drug-induced liver injury. NEW & NOTEWORTHY The organic solute transporter OSTα/β is highly expressed in hepatocytes of liver tissue obtained from patients with nonalcoholic steatohepatitis and primary biliary cholangitis. OSTα/β substrates exhibit rapid, linear, and concentration-driven transport in an OSTα/β-overexpressing cell line. Drugs associated with hepatotoxicity modulate OSTα/β-mediated taurocholate transport. These data suggest that hepatic OSTα/β plays an essential role in patients with cholestasis and may have important clinical implications for bile acid and drug disposition.

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Free fatty acids, not triglycerides, are associated with non-alcoholic liver injury progression in high fat diet induced obese rats

Lipids in Health and Disease ◽

10.1186/s12944-016-0194-7 ◽

2016 ◽

Vol 15 (1) ◽

Cited By ~ 47

Author(s):

Jiali Liu ◽

Lina Han ◽

Leilei Zhu ◽

Yerong Yu

Keyword(s):

Fatty Acids ◽

Liver Injury ◽

Free Fatty Acids ◽

High Fat Diet ◽

Alcoholic Liver Injury ◽

High Fat ◽

Obese Rats ◽

Injury Progression

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Activation of mTORC1 by Free Fatty Acids Suppresses LAMP2 and Autophagy Function via ER Stress in Alcohol-Related Liver Disease

Cells ◽

10.3390/cells10102730 ◽

2021 ◽

Vol 10 (10) ◽

pp. 2730

Author(s):

Wei Guo ◽

Wei Zhong ◽

Liuyi Hao ◽

Xinguo Sun ◽

Zhanxiang Zhou

Keyword(s):

Fatty Acids ◽

Liver Disease ◽

Liver Injury ◽

Er Stress ◽

Free Fatty Acids ◽

Cell Injury ◽

Autophagy Flux ◽

Mtorc1 Signaling ◽

Related Liver Disease ◽

Mtorc1 Activation

Alcohol-related liver disease (ALD) is characterized by accumulation of hepatic free fatty acids (FFAs) and liver injury. The present study aimed to investigate if mechanistic target of rapamycin complex 1 (mTORC1) plays a role in FFA-induced organelle dysfunction, thereby contributing to the development of ALD. Cell studies were conducted to define the causal role and underlying mechanism of FFA-activated mTORC1 signaling in hepatocellular cell injury. C57BL/6J wild-type mice were subjected to chronic alcohol feeding with or without rapamycin to inhibit mTORC1 activation. We revealed that palmitic acid (PA)-induced ER stress and suppression of LAMP2 and autophagy flux were mTORC1-dependent as rapamycin reversed such deleterious effects. C/EBP homologous protein (CHOP) was downstream of ATF4 which partially modulated LAMP2. Supplementation with rapamycin to alcohol-fed mice attenuated mTORC1 activation and ER stress, restored LAMP2 protein, and improved autophagy, leading to amelioration of alcohol-induced liver injury. Induction of mTORC1 signaling and CHOP were also detected in the liver of patients with severe alcoholic hepatitis. This study demonstrates that hepatic FFAs play a crucial role in the pathogenesis of ALD by activating mTORC1 signaling, thereby inducing ER stress and suppressing LAMP2-autophagy flux pathway, which represents an important mechanism of FFA-induced hepatocellular injury.

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Skeleton interoception regulates bone and fat metabolism through hypothalamic neuroendocrine NPY

eLife ◽

10.7554/elife.70324 ◽

2021 ◽

Vol 10 ◽

Author(s):

Xiao Lv ◽

Feng Gao ◽

Tuo Peter Li ◽

Peng Xue ◽

Xiao Wang ◽

...

Keyword(s):

Fatty Acids ◽

Bone Formation ◽

Free Fatty Acids ◽

Leucine Zipper ◽

Sensory Nerve ◽

Bone Homeostasis ◽

Y1 Receptor ◽

Small Heterodimer Partner ◽

The Central Nervous System ◽

Leucine Zipper Protein

The central nervous system regulates activity of peripheral organs through interoception. In our previous study, we have demonstrated that PGE2/EP4 skeleton interception regulate bone homeostasis. Here, we show that ascending skeleton interoceptive signaling downregulates expression of hypothalamic neuropeptide Y (NPY) and induce lipolysis of adipose tissue for osteoblastic bone formation. Specifically, the ascending skeleton interoceptive signaling induces expression of small heterodimer partner-interacting leucine zipper protein (SMILE) in the hypothalamus. SMILE binds to pCREB as a transcriptional heterodimer on Npy promoters to inhibit NPY expression. Knockout of EP4 in sensory nerve increases expression of NPY causing bone catabolism and fat anabolism. Importantly, inhibition of NPY Y1 receptor (Y1R) accelerated oxidation of free fatty acids in osteoblasts and rescued bone loss in AvilCre:Ptger4fl/fl mice. Thus, downregulation of hypothalamic NPY expression lipolyzes free fatty acids for anabolic bone formation through a neuroendocrine descending interoceptive regulation.

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Bile acid sequestration reverses liver injury and prevents progression of nonalcoholic steatohepatitis in Western diet–fed mice

Journal of Biological Chemistry ◽

10.1074/jbc.ra119.011913 ◽

2020 ◽

Vol 295 (14) ◽

pp. 4733-4747 ◽

Cited By ~ 5

Author(s):

Shogo Takahashi ◽

Yuhuan Luo ◽

Suman Ranjit ◽

Cen Xie ◽

Andrew E. Libby ◽

...

Keyword(s):

Liver Disease ◽

Bile Acid ◽

Liver Injury ◽

Fatty Liver ◽

Bile Acids ◽

Nonalcoholic Steatohepatitis ◽

Fatty Liver Disease ◽

Liver Diseases ◽

Nonalcoholic Fatty Liver ◽

Bile Acid Sequestrants

Nonalcoholic fatty liver disease is a rapidly rising problem in the 21st century and is a leading cause of chronic liver disease that can lead to end-stage liver diseases, including cirrhosis and hepatocellular cancer. Despite this rising epidemic, no pharmacological treatment has yet been established to treat this disease. The rapidly increasing prevalence of nonalcoholic fatty liver disease and its aggressive form, nonalcoholic steatohepatitis (NASH), requires novel therapeutic approaches to prevent disease progression. Alterations in microbiome dynamics and dysbiosis play an important role in liver disease and may represent targetable pathways to treat liver disorders. Improving microbiome properties or restoring normal bile acid metabolism may prevent or slow the progression of liver diseases such as NASH. Importantly, aberrant systemic circulation of bile acids can greatly disrupt metabolic homeostasis. Bile acid sequestrants are orally administered polymers that bind bile acids in the intestine, forming nonabsorbable complexes. Bile acid sequestrants interrupt intestinal reabsorption of bile acids, decreasing their circulating levels. We determined that treatment with the bile acid sequestrant sevelamer reversed the liver injury and prevented the progression of NASH, including steatosis, inflammation, and fibrosis in a Western diet–induced NASH mouse model. Metabolomics and microbiome analysis revealed that this beneficial effect is associated with changes in the microbiota population and bile acid composition, including reversing microbiota complexity in cecum by increasing Lactobacillus and decreased Desulfovibrio. The net effect of these changes was improvement in liver function and markers of liver injury and the positive effects of reversal of insulin resistance.

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Pannexin1 contributes to pathophysiological ATP release in lipoapoptosis induced by saturated free fatty acids in liver cells

AJP Cell Physiology ◽

10.1152/ajpcell.00175.2012 ◽

2012 ◽

Vol 303 (10) ◽

pp. C1034-C1044 ◽

Cited By ~ 35

Author(s):

Feng Xiao ◽

Shar L. Waldrop ◽

Al-karim Khimji ◽

Gordan Kilic

Keyword(s):

Fatty Acids ◽

Liver Injury ◽

Free Fatty Acids ◽

Atp Release ◽

Liver Cells ◽

Extracellular Atp ◽

Pcr Analysis ◽

Dependent Manner ◽

Hepatic Inflammation ◽

Atp Concentration

Hepatocyte lipoapoptosis induced by saturated free fatty acids (FFA) contributes to hepatic inflammation in lipotoxic liver injury, and the cellular mechanisms involved have not been defined. Recent studies have shown that apoptosis in nonhepatic cells stimulates ATP release via activation of pannexin1 (panx1), and extracellular ATP functions as a proinflammatory signal for recruitment and activation of the inflammatory cells. However, it is not known whether lipoapoptosis stimulates ATP release in liver cells. We found that lipoapoptosis induced by saturated FFA stimulated ATP release in liver cells that increased extracellular ATP concentration by more than fivefold above the values observed in healthy cells. This sustained pathophysiological ATP release was not dependent on caspase-3/7 activation. Inhibition of c-Jun NH2-terminal kinase (JNK), a key mediator of lipoapoptosis, with SP600125 blocked pathophysiological ATP release in a dose-dependent manner. RT-PCR analysis indicated that panx1 is expressed in hepatocytes and multiple liver cell lines. Notably, inhibition of panx1 expression with short hairpin (sh)RNA inhibited in part pathophysiological ATP release. Moreover, lipoapoptosis stimulated uptake of a membrane impermeable dye YoPro-1 (indicative of panx1 activation), which was inhibited by panx1 shRNA, probenecid, and mefloquine. These results suggest that panx1 contributes to pathophysiological ATP release in lipoapoptosis induced by saturated FFA. Thus panx1 may play an important role in hepatic inflammation by mediating an increase in extracellular ATP concentration in lipotoxic liver injury.

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Dietary production and dissolution of cholesterol gallstones in the mouse

American Journal of Physiology-Legacy Content ◽

10.1152/ajplegacy.1965.209.3.473 ◽

1965 ◽

Vol 209 (3) ◽

pp. 473-478 ◽

Cited By ~ 31

Author(s):

Fred T. Caldwell ◽

Katherine Levitsky ◽

Barbara Rosenberg

Keyword(s):

Fatty Acids ◽

Bile Acid ◽

Free Fatty Acids ◽

Histological Change ◽

Histological Changes ◽

Cholesterol Gallstones ◽

Initial Rise ◽

Purina Laboratory ◽

Bile Cholesterol ◽

Chemical Response

Groups of animals fed lithogenic diets were sacrificed at intervals, with serum and bladder bile obtained. Bile was analyzed for bile acids, lecithin, free fatty acids, and cholesterol concentrations, serum for cholesterol and free fatty acids. Gall bladders were also examined for histological change. The chemical response to the diets was a prompt increment in serum and bile cholesterol concentrations. After an initial rise, bile acid content of bile decreased, resulting in a fall in bile acid-to-cholesterol ratios to the point of cholesterol precipitation. Stones once formed dissolved when animals harboring stones were fed Purina laboratory chow. Histological changes appeared in the gall bladder after 2 weeks on the diets and were progressive.

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